Cyclic 1-(acyloxy)-alkyl prodrugs of GABA analogs, compositions and uses thereof

ABSTRACT

The present invention provides cyclic 1-(acyloxy)-alkyl prodrugs of GABA analogs, methods of making cyclic 1-(acyloxy)-alkyl prodrugs of GABA analogs and compositions of cyclic 1-(acyloxy)-alkyl prodrugs of GABA analogs. The present invention also provides methods of using cyclic 1-(acyloxy)-alkyl prodrugs of GABA analogs and compositions of cyclic 1-(acyloxy)-alkyl prodrugs of GABA analogs.

[0001] This application claims the benefit under 35 U.S.C. § 119(e) ofU.S. Provisional Application No. 60/327,297, filed Mar. 20, 2002, thecontents of which are incorporated by reference herein in theirentirety.

1. FIELD OF THE INVENTION

[0002] The present invention relates generally to cyclic1-(acyloxy)-alkyl prodrugs of GABA analogs, methods of making cyclic1-(acyloxy)-alkyl prodrugs of GABA analogs and compositions of cyclic1-(acyloxy)-alkyl prodrugs of GABA analogs. The present invention alsorelates generally to methods of using cyclic 1-(acyloxy)-alkyl prodrugsof GABA analogs and compositions of cyclic 1-(acyloxy)-alkyl prodrugs ofGABA analogs. More particularly, the present invention relates to cyclic1-(acyloxy)-alkyl prodrugs of gabapentin and pregabalin, methods ofmaking cyclic 1-(acyloxy)-alkyl prodrugs of gabapentin and pregabalin,compositions of 1-(acyloxy)-alkyl prodrugs of gabapentin and pregabalin,methods of using cyclic 1-(acyloxy)-alkyl prodrugs of gabapentin andpregabalin and compositions of cyclic 1-(acyloxy)-alkyl prodrugs ofgabapentin and pregabalin.

2. BACKGROUND OF THE INVENTION

[0003] Gamma (“γ”)-aminobutyric acid (“GABA”) is one of the majorinhibitory transmitters in the central nervous system of mammals. GABAis not transported efficiently into the brain from the bloodstream(i.e., GABA does not effectively cross the blood-brain barrier).Consequently, brain cells provide virtually all of the GABA found in thebrain (GABA is biosynthesized by decarboxylation of glutamic acid withpyridoxal phosphate).

[0004] GABA regulates neuronal excitability through binding to specificmembrane proteins (i.e., GABAA receptors), which results in opening ofan ion channel. The entry of chloride ion through the ion channel leadsto hyperpolarization of the recipient cell, which consequently preventstransmission of nerve impulses to other cells. Low levels of GABA havebeen observed in individuals suffering from epileptic seizures, motiondisorders (e.g., multiple sclerosis, action tremors, tardivedyskinesia), panic, anxiety, depression, alcoholism and manic behavior.

[0005] The implication of low GABA levels in a number of common diseasestates and/or common medical disorders has stimulated intensive interestin preparing GABA analogs, which have superior pharmaceutical propertiesin comparison to GABA (e.g., the ability to cross the blood brainbarrier). Accordingly, a number of GABA analogs, with considerablepharmaceutical activity have been synthesized in the art (See, e.g.,Satzinger et al., U.S. Pat. No. 4,024,175; Silverman et al., U.S. Pat.No. 5,563,175; Horwell et al., U.S. Pat. No. 6,020,370; Silverman etal., U.S. Pat. No. 6,028,214; Horwell et al., U.S. Pat. No. 6,103,932;Silverman et al., U.S. Pat. No. 6,117,906; Silverman, InternationalApplication No. WO 92/09560; Silverman et al., International ApplicationNo. WO 93/23383; Horwell et al., International Application No. WO97/29101, Horwell et al., International Application No. WO 97/33858;Horwell et al., International Application No. WO 97/33859; Bryans etal., International Application No. WO 98/17627; Guglietta et al.,International Application No. WO 99/08671; Bryans et al., InternationalApplication No. WO 99/21824; Bryans et al., International ApplicationNo. WO 99/31057; Belliotti et al., International Application No. WO99/31074; Bryans et al., International Application No. WO 99/31075;Bryans et al., International Application No. WO 99/61424; Bryans et al.,International Application No. WO 00/15611; Bryans, InternationalApplication No. WO 00/31020; Bryans et al., International ApplicationNo. WO 00/50027; and Bryans et al, International Application No. WO02/00209).

[0006] Pharmaceutically important GABA analogs include, for example,gabapentin 1, pregabalin 3, vigabatrin 5, and baclofen 7, shown above.Gabapentin is a lipophilic GABA analog that can pass through theblood-brain barrier, which has been used to clinically treat epilepsysince 1994. Gabapentin also has potentially useful therapeutic effectsin chronic pain states (e.g., neuropathic pain, muscular and skeletalpain), psychiatric disorders (e.g., panic, anxiety, depression,alcoholism and manic behavior), movement disorders (e.g., multiplesclerosis, action tremors, tardive dyskinesia), etc. (Magnus, Epilepsia,1999, 40:S66-S72). Currently, gabapentin is also used in the clinicalmanagement of neuropathic pain. Pregabalin, which possesses greaterpotency in pre-clinical models of pain and epilepsy than gabapentin ispresently in Phase III clinical trials.

[0007] A significant problem with many GABA analogs is intramolecularreaction of the y amino group with the carboxyl functionality to formthe γ-lactam as exemplified for gabapentin below. Formation of γ-lactam9 presents serious difficulties in formulating gabapentin because of itstoxicity. For example, gabapentin has a toxicity (LD₅₀, mouse) of morethan 8000 mg/kg, while the corresponding lactam 9 has a toxicity (LD₅₀,mouse) of 300 mg/kg. Consequently, formation of side products such aslactams during synthesis of GABA analogs and/or formulation and/orstorage of either GABA analogs or compositions of GABA analogs must beminimized for safety reasons (particularly, in the case of gabapentin).

[0008] The problem of lactam contamination of GABA analogs, particularlyin the case of gabapentin, has been partially overcome through use ofspecial additional purification steps, precise choice of adjuvantmaterials in pharmaceutical compositions and careful control procedures(Augurt et al., U.S. Pat. No. 6,054,482). However, attempts to preventlactam contamination have not been entirely successful, in eithersynthesis or storage of GABA analogs such as gabapentin or compositionsthereof.

[0009] Rapid systemic clearance is another significant problem with manyGABA analogs including gabapentin, which consequently require frequentdosing to maintain a therapeutic or prophylactic concentration in thesystemic circulation (Bryans et al., Med. Res. Rev., 1999, 19, 149-177).For example, typical dosing regimens of 300-600 mg t.i.d. of gabapentinare typically used for anticonvulsive therapy. Higher doses.(1800-3600mg/d in divided doses) are typically used for the treatment ofneuropathic pain states.

[0010] Sustained released formulations are a conventional solution tothe problem of rapid systemic clearance, as is well known to those ofskill in the art (See, e.g., “Remington's Pharmaceutical Sciences,”Philadelphia College of Pharmacy and Science, 17th Edition, 1985).Osmotic delivery systems are also recognized methods for sustained drugdelivery (See, e.g., Verma et al., Drug Dev. Ind. Pharm., 2000,26:695-708).

[0011] Many GABA analogs, including gabapentin and pregabalin, are notabsorbed via the large intestine. Rather, these compounds are typicallyabsorbed in the small intestine by the large neutral amino acidtransporter (“LNAA”) (Jezyk et al., Pharm. Res., 1999, 16, 519-526). Therapid passage of conventional dosage forms through the proximalabsorptive region of the gastrointestinal tract has prevented thesuccessful application of sustained release technologies to many GABAanalogs.

[0012] Thus, there is a significant need for effective sustained releaseversions of GABA analogs to minimize increased dosing frequency due torapid systemic clearance of these compounds. There is also a need forpure GABA analogs, (particularly gabapentin and pregablin analogs) whichare substantially pure and do not spontaneously lactamize during eitherformulation or storage.

3. SUMMARY OF THE INVENTION

[0013] The present invention addresses these and other needs byproviding cyclic 1-(acyloxy)-alkyl prodrugs of GABA analogs,compositions of cyclic 1-(acyloxy)-alkyl prodrugs of GABA analogs andmethods for making cyclic 1-(acyloxy)-alkyl prodrugs of GABA analogs.The present invention also provides methods for using cyclic1-(acyloxy)-alkyl prodrugs of GABA analogs, methods for usingcompositions of cyclic 1-(acyloxy)-alkyl prodrugs of GABA analogs andcompositions of cyclic 1-(acyloxy)-alkyl prodrugs of GABA analogs fortreating or preventing common diseases and/or disorders.

[0014] Generally, the compounds of the invention have a cyclicacyloxyalkoxycarbonyl promoiety attached to the γ amino group of GABAanalogs. The promoiety may be directly attached to the γ amino group ofa GABA analog, or optionally, may be attached to the amino group of anα-amino acid promoiety, which may be acylated to the γ amino group ofthe GABA analog.

[0015] The compounds of the invention may also have a promoiety attachedto the carboxyl group of GABA analogs. The carboxyl promoiety may be anester or thioester group. A wide variety of ester or thioester groupsmay be used to form carboxyl promoieties.

[0016] The compounds of the invention may include as many as threepromoieties, including one carboxyl promoiety and up to two promoietiesattached in sequence to the γ amino group (i.e., such that eachpromoiety is sequentially cleaved from the N-terminal end of the GABAanalog). The compounds of the invention will preferably, contain twoamino promoieties and one carboxyl promoiety, two amino promoieties, oneamino promoiety and one carboxyl promoiety or one amino promoiety.Preferably, in those compounds of the invention which contain both anamino promoiety and a carboxyl promoiety, the carboxyl promoiety ishydrolyzed prior to the complete cleavage of the promoiety (ies)attached to the amine group.

[0017] In a first aspect the present invention provides compounds ofstructural formula (I):

[0018] or a pharmaceutically acceptable salt, hydrate or solvatethereof, wherein:

[0019] n is 0 or 1;

[0020] Y is O or S;

[0021] X is alkyldiyl, substituted alkyldiyl, arylalkyldiyl, substitutedarylalkyldiyl, aryldiyl, substituted aryldiyl, cycloheteroalkyldiyl,substituted cycloheteroalkyldiyl, heteroaryldiyl, substitutedheteroaryldiyl, heteroarylalkyldiyl, substituted heteroarylalkyldiyl,heteroalkyldiyl or substituted heteroalkyldiyl;

[0022] R⁴⁷ is hydrogen, alkyl, substituted alkyl, arylalkyl orsubstituted arylalkyl;

[0023] R² is hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, acyl, substituted acyl, acylamino, substituted acylamino,alkylamino, substituted alkylamino, alklysulfinyl, substitutedalkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio,substituted alkylthio, alkoxycarbonyl, substituted alkylthio, aryl,substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substitutedaryloxy, carbamoyl, substituted carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, substituted dialkylamino, halo, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy,heteroaryloxy, substituted heteroaryloxy, or optionally, R⁴⁷ and R²taken together are alkyldiyl or substituted alkyldiyl;

[0024] R³ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl and substituted heteroarylalkyl;

[0025] R⁴ and R⁵ are independently hydrogen, alkyl, substituted alkyl,acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl or optionally, R⁴ and R⁵taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl,substituted heteroalkyldiyl, or together with the carbon atom to whichthey are attached form a bridged cycloalkyl ring;

[0026] R⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; and

[0027] R⁴⁸ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl.

[0028] In a second aspect, the present invention provides compositionsof compounds of the invention. The compositions generally comprise oneor more compounds of the invention, pharmaceutically acceptable salts,hydrates or solvates thereof and a pharmaceutically acceptable diluent,carrier, excipient and adjuvant. The choice of diluent, carrier,excipient and adjuvant will depend upon, among other factors, thedesired mode of administration.

[0029] In a third aspect, the present invention provides methods fortreating or preventing epilepsy, depression, anxiety, psychosis,faintness attacks, hypokinesia, cranial disorders, nuerodegenerativedisorders, panic, pain (especially, neuropathic pain, post-herpeticpain, and muscular and skeletal pain), inflammatory disease (i.e.,arthritis), insomnia, gastrointestinal disorders or ethanol withdrawalsyndrome. The methods generally involve administering to a patient inneed of such treatment or prevention a therapeutically effective amountof a compound and/or composition of the invention.

[0030] In a fourth aspect, the current invention provides compositionsfor treating or preventing epilepsy, depression, anxiety, psychosis,faintness attacks, hypokinesia, cranial disorders, nuerodegenerativedisorders, panic, pain (especially, neuropathic pain, post-herpeticpain, and muscular and skeletal pain), inflammatory disease (i.e.,arthritis), insomnia, gastrointestinal disorders or ethanol withdrawalsyndrome in a patient in need of such treatment or prevention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Definitions

[0031] “Compounds of the invention” refers to compounds encompassed bygeneric formulae disclosed herein and includes any specific compoundswithin that formula whose structure is disclosed herein. The compoundsof the invention may be identified either by their chemical structureand/or chemical name. When the chemical structure and chemical nameconflict, the chemical structure is determinative of the identity of thecompound. The compounds of the invention may contain one or more chiralcenters and/or double bonds and therefore, may exist as stereoisomers,such as double-bond isomers (i.e., geometric isomers), enantiomers ordiastereomers. Accordingly, the chemical structures depicted hereinencompass all possible enantiomers and stereoisomers of the illustratedcompounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds of theinvention may also exist in several tautomeric forms including the enolform, the keto form and mixtures thereof. Accordingly, the chemicalstructures depicted herein encompass all possible tautomeric forms ofthe illustrated compounds. The compounds of the invention also includeisotopically labeled compounds where one or more atoms have an atomicmass different from the atomic mass conventionally found in nature.Examples of isotopes that may be incorporated into the compounds of theinvention include, but are not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl. Further, it should be understood, whenpartial structures of the compounds of the invention are illustrated,that brackets indicate the point of attachment of the partial structureto the rest of the molecule.

[0032] “Composition of the invention” refers to at least one compound ofthe invention and a pharmaceutically acceptable vehicle, with which thecompound is administered to a patient. When administered to a patient,the compounds of the invention are administered in isolated form, whichmeans separated from a synthetic organic reaction mixture.

[0033] “Active transport or active transport process” refers to themovement of molecules across cellular membranes that:

[0034] a) is directly or indirectly dependent on an energy mediatedprocess (i.e., driven by ATP hydrolysis, ion gradient, etc.);

[0035] or

[0036] b) occurs by facilitated diffusion mediated by interaction withspecific transporter proteins.

[0037] “Transporter protein” refers to a protein that has a direct orindirect role in transporting a molecule into and/or through a cell. Forexample, transporter protein includes, but is not limited to, solutecarrier transporters, co-transporters, counter transporters, uniporters,symporters, antiporters, pumps, equilibrative transporters,concentrative transporters and other proteins, which mediate activetransport, energy-dependent transport, facilitated diffusion, exchangemechanisms and specific absorption mechanisms. Transporter protein, alsoincludes but is not limited to, membrane-bound proteins that recognize asubstrate and effect its entry into or exit from a cell by acarrier-mediated transporter or by receptor-mediated transport.Transporter protein, also includes but is not limited to,intracellularly expressed proteins that participate in trafficking ofsubstrates through or out of a cell. Transporter protein, also includesbut is not limited to, proteins or glycoproteins exposed on the surfaceof a cell that do not directly transport a substrate but bind to thesubstrate holding it in proximity to a receptor or transporter proteinthat effects entry of the substrate into or through the cell. Examplesof carrier proteins include: the intestinal and liver bile acidtransporters, dipeptide transporters, oligopeptide transporters, simplesugar transporters (e.g., SGLT1), phosphate transporters,monocarboxcylic acid transporters, P-glycoprotein transporters, organicanion transporters (OAT), and organic cation transporters. Examples ofreceptor-mediated transport proteins include: viral receptors,immunoglobulin receptors, bacterial toxin receptors, plant lectinreceptors, bacterial adhesion receptors, vitamin transporters andcytokine growth factor receptors.

[0038] “Passive diffusion” refers to uptake of an agent that is notmediated by a specific transporter protein. An agent that issubstantially incapable of passive diffusion has a permeabilty across astandard cell monolayer (e.g., Caco-2) in vitro of less than 5×10⁻⁶cm/sec, and usually less than 1×10⁻⁶ cm/sec (in the absence of an effluxmechanism).

[0039] “Alkyl” refers to a saturated or unsaturated, branched,straight-chain or cyclic monovalent hydrocarbon radical derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkane, alkene or alkyne. Typical alkyl groups include, but are notlimited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propylssuch as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl;cycloprop-2-en-1-yl, prop-1-yn-1-yl , prop-2-yn-1-yl, etc.; butyls suchas butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

[0040] The term “alkyl” is specifically intended to include groupshaving any degree or level of saturation, i.e., groups havingexclusively single carbon-carbon bonds, groups having one or more doublecarbon-carbon bonds, groups having one or more triple carbon-carbonbonds and groups having mixtures of single, double and triplecarbon-carbon bonds. Where a specific level of saturation is intended,the expressions “alkanyl,” “alkenyl,” and “alkynyl” are used.Preferably, an alkyl group comprises from 1 to 20 carbon atoms, morepreferably, from 1 to 10 carbon atoms.

[0041] “Alkanyl” refers to a saturated branched, straight-chain orcyclic alkyl radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane. Typical alkanyl groups include,but are not limited to, methanyl; ethanyl; propanyls such aspropan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanylssuch as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl(isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; andthe like.

[0042] “Alkenyl” refers to an unsaturated branched, straight-chain orcyclic alkyl radical having at least one carbon-carbon double bondderived by the removal of one hydrogen atom from a single carbon atom ofa parent alkene. The group may be in either the cis or transconformation about the double bond(s). Typical alkenyl groups include,but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl ,prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl,cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.;and the like.

[0043] “Alkynyl” refers to an unsaturated branched, straight-chain orcyclic alkyl radical having at least one carbon-carbon triple bondderived by the removal of one hydrogen atom from a single carbon atom ofa parent alkyne. Typical alkynyl groups include, but are not limited to,ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.;butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; andthe like.

[0044] “Alkyldiyl” refers to a saturated or unsaturated, branched,straight-chain or cyclic divalent hydrocarbon group derived by theremoval of one hydrogen atom from each of two different carbon atoms ofa parent alkane, alkene or alkyne, or by the removal of two hydrogenatoms from a single carbon atom of a parent alkane, alkene or alkyne.The two monovalent radical centers or each valency of the divalentradical center can form bonds with the same or different atoms. Typicalalkyldiyl groups include, but are not limited to methandiyl; ethyldiylssuch as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl;propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl,propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, diyl,prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl,prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl,cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as,butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl,butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl,cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl,but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl,but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl,2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl,buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl,cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl,cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl,but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.; andthe like. Where specific levels of saturation are intended, thenomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used.Preferably, an alkyldiyl group is (C₁-C₂₀) alkyldiyl, more preferably,C₁-C₂₀) alkyldiyl. Also preferred are saturated acyclic alkanyldiylgroups in which the radical centers are at the terminal carbons, e.g.,methandiyl (methano); ethan-1,2-diyl (ethano); propan-1,3-diyl(propano); butan-1,4-diyl (butano); and the like (also referred to asalkylenos, defined infra).

[0045] “Alkyleno” refers to a straight-chain alkyldiyl group having twoterminal monovalent radical centers derived by the removal of onehydrogen atom from each of the two terminal carbon atoms ofstraight-chain parent alkane, alkene or alkyne. Typical alkyleno groupsinclude, but are not limited to, methano; ethylenos such as ethano,etheno, ethyno; propylenos such as propano, prop[1]eno, propa[1,2]dieno,prop[1]yno, etc.; butylenos such as butano, but[1]eno, but[2]eno,buta[1,3]dieno, but[1]yno, but[2]yno, but[1,3]diyno, etc.; and the like.Where specific levels of saturation are intended, the nomenclaturealkano, alkeno and/or alkyno is used.

[0046] “Acyl” refers to a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein. Representative examples include, butare not limited to formyl, acetyl, cylcohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

[0047] “Acylamino” (or alternatively “acylamido”) refers to a radical—NR′C(O)R, where R′ and R are each independently hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein. Representative examples include, butare not limited to, formylamino, acetylamino (i.e., acetamido),cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino(i.e., benzamido), benzylcarbonylamino and the like.

[0048] “Acyloxy” refers to a radical —OC(O)R, where R is hydrogen,alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,heteroaryl or heteroarylalkyl, as defined herein. Representativeexamples include, but are not limited to, acetoxy, butoxy, benzoyloxyand the like.

[0049] “Alkylamino” means a radical —NHR where R represents an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylamino, ethylamino, 1-methylethylamino,cyclohexyl amino and the like.

[0050] “Alkoxy” refers to a radical —OR where R represents an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy andthe like.

[0051] “Alkoxycarbonyl” refers to a radical —C(O)-alkoxy where alkoxy isas defined herein.

[0052] “Alkylsulfonyl” refers to a radical —S(O)₂R where R is an alkylor cycloalkyl group as defined herein. Representative examples include,but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl,butylsulfonyl and the like.

[0053] “Alkylsulfinyl” refers to a radical —S(O)R where R is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl,butylsulfinyl and the like.

[0054] “Alkylthio” refers to a radical —SR where R is an alkyl orcycloalkyl group as defined herein that may be optionally substituted asdefined herein. Representative examples include, but are not limited tomethylthio, ethylthio, propylthio, butylthio and the like.

[0055] “Amino” refers to the radical —NH₂.

[0056] “Aryl” refers to a monovalent aromatic hydrocarbon group derivedby the removal of one hydrogen atom from a single carbon atom of aparent aromatic ring system. Typical aryl groups include, but are notlimited to, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. Preferably, an arylgroup comprises from 5 to 20 carbon atoms, more preferably between 5 to12 carbon atoms.

[0057] “Aryldiyl” refers to a divalent aromatic hydrocarbon groupderived by the removal of one hydrogen atom from each of two differentcarbon atoms of a parent aromatic ring system or by the removal of twohydrogen atoms from a single carbon atom of a parent aromatic ringsystem. The two monovalent radical centers or each valency of thedivalent center can form bonds with the same or different atom(s).Typical aryldiyl groups include, but are not limited to, divalent groupsderived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, coronene, fluoranthene,fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene,indane, indene, naphthalene, octacene, octaphene, octalene, ovalene,penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene,phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene,triphenylene, trinaphthalene, and the like. In preferred embodiments,the aryldiyl group is (C₅-C₂₀) aryldiyl, with (C₅-C₁₂) being even morepreferred.

[0058] “Arylalkyl” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl group. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylalkenyl and/or arylalkynyl is used. Preferably, anarylalkyl group is (C₆-C₃₀) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₁₀) and the aryl moiety is(C₅-C₂₀), more preferably, an arylalkyl group is (C₆-C₂₀) arylalkyl,e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is(C₁-C₈) and the aryl moiety is (C₅-C₁₂).

[0059] “Arylalkyldiyl” refers to an arylalkyl group in which two of thearylalkyl group's hydrogen atoms have been replaced by covalent bonds.The two covalent bonds can be to the alkyl moiety of the arylalkylgroup, as illustrated in the phenethylene group shown below:

[0060] Alternatively, one of the covalent bonds can be to the alkylmoiety of the arylalkyl group and the other covalent bond can be to thearyl moiety of the arylalkyl group, as illustrated in the phenethylenegroup shown below:

[0061] “Arylalkyloxy” refers to an —O-arylalkyl group where arylalkyl isas defined herein.

[0062] “Aryloxycarbonyl” refers to a radical —C(O)—O-aryl where aryl isas defined herein.

[0063] “Bridged cycloalkyl” refers to a radical selected from the groupconsisting of

[0064] wherein:

[0065] A is (CR³⁵R³⁶)_(b);

[0066] R³⁵ and R³⁶ are independently selected from the group consistingof hydrogen and methyl;

[0067] R³³ and R³⁴ are independently selected from the group consistingof hydrogen and methyl;

[0068] b is an integer from 1 to 4; and

[0069] c is an integer from 0 to 2.

[0070] “Carbamoyl” refers to the radical —C(O)N(R)₂ where each R groupis independently hydrogen, alkyl, cycloalkyl or aryl as defined herein,which may be optionally substituted, as defined herein.

[0071] “Carboxy” means the radical —C(O)OH.

[0072] “Cyano” means the radical —CN.

[0073] “Cycloalkyl” refers to a saturated or unsaturated cyclic alkylradical. Where a specific level of saturation is intended, thenomenclature “cycloalkanyl” or “cycloalkenyl” is used. Typicalcycloalkyl groups include, but are not limited to, groups derived fromcyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like.Preferably, the cycloalkyl group is (C₃-C₁₀) cycloalkyl, more preferably(C₃-C₇) cycloalkyl.

[0074] “Cycloheteroalkyl” refers to a saturated or unsaturated cyclicalkyl radical in which one or more carbon atoms (and any associatedhydrogen atoms) are independently replaced with the same or differentheteroatom. Typical heteroatoms to replace the carbon atom(s) include,but are not limited to, N, P, O, S, Si, etc. Where a specific level ofsaturation is intended, the nomenclature “cycloheteroalkanyl” or“cycloheteroalkenyl” is used. Typical cycloheteroalkyl groups include,but are not limited to, groups derived from epoxides, imidazolidine,morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine,quinuclidine, and the like.

[0075] “Cycloheteroalkyldiyl” refers to a saturated or unsaturatedcyclic alkyl diradical in which one or more carbon atoms (and anyassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatom. Typical heteroatoms to replace the carbon atom(s)include, but are not limited to, N, P, O, S, Si, etc. Where a specificlevel of saturation is intended, the nomenclature“cycloheteroalkanyldiyl” or “cycloheteroalkenyldiyl” is used.

[0076] “Cycloheteroalkyloxycarbonyl” refers to a radical —C(O)—OR whereR is cycloheteroalkyl is as defined herein.

[0077] “Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl or cycloalkyl group as defined herein. Representativeexamples include, but are not limited to, dimethylamino,methylethylamino, di-(1-methylethyl)amino, (cyclohexyl)(methyl)amino,(cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino and the like.

[0078] “Halo” means fluoro, chloro, bromo, or iodo.

[0079] “Heteroalkyloxy” means an —O-heteroalkyl group where heteroalkylis as defined herein.

[0080] “Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkynyl” referto alkyl, alkanyl, alkenyl and alkynyl radical, respectively, in whichone or more of the carbon atoms (and any associated hydrogen atoms) areeach independently replaced with the same or different heteroatomicgroups. Typical heteroatomic groups include, but are not limited to,—O—,—S—, —O—O—, —S—S—, —O—S—, —NR′—, ═N—N═, —N═N—, —N═N—, —N═N—NR′—, —PH—,—P(O)₂—, —O—P(O)₂—, —S(O)—, —S(O)₂—, —SnH₂— and the like, where R′ ishydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,aryl or substituted aryl.

[0081] “Heteroaryl” refers to a monovalent heteroaromatic radicalderived by the removal of one hydrogen atom from a single atom of aparent heteroaromatic ring system. Typical heteroaryl groups include,but are not limited to, groups derived from acridine, arsindole,carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole,indazole, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,phenanthroline, phenazine, phthalazine, pteridine, purine, pyran,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. Preferably, the heteroaryl group is between 5-20 memberedheteroaryl, more preferably between 5-10 membered heteroaryl. Preferredheteroaryl groups include those derived from thiophene, pyrrole,benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole,oxazole and pyrazine.

[0082] “Heteroaryldiyl” refers to a divalent heteroaromatic groupderived by the removal of one hydrogen atom from each of two differentatoms of a parent heteroaromatic ring system or by the removal of twohydrogen atoms from a single atom of a parent heteroaromatic ringsystem. The two monovalent radical centers or each valency of the singledivalent center can form bonds with the same or different atom(s).Typical heteroaryldiyl groups include, but are not limited to, divalentgroups derived from acridine, arsindole, carbazole, ∃-carboline,chromane, chromene, cinnoline, furan, imidazole, indazole, indole,indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. In preferred embodiments,the heteroaryldiyl group is 5-20 membered heteroaryldiyl, with 5-10membered being particularly preferred. The most preferred heteroaryldiylgroups are divalent groups derived from the preferred heteroarylsthiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine,quinoline, imidazole, oxazole and pyrazine.

[0083] “Heteroaryloxycarbonyl” refers to a radical —C(O)—OR where R isheteroaryl as defined herein.

[0084] “Heteroarylalkyl” refers to an acyclic alkyl group in which oneof the hydrogen atoms bonded to a carbon atom, typically a terminal orsp³ carbon atom, is replaced with a heteroaryl group. Where specificalkyl moieties are intended, the nomenclature heteroarylalkanyl,heteroarylalkenyl and/or heterorylalkynyl is used. In preferredembodiments, the heteroarylalkyl group is a 6-30 memberedheteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of theheteroarylalkyl is 1-10 membered and the heteroaryl moiety is a5-20-membered heteroaryl, more preferably, 6-20 memberedheteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of theheteroarylalkyl is 1-8 membered and the heteroaryl moiety is a5-12-membered heteroaryl.

[0085] “Heteroarylalkyldiyl” refers to an acyclic alkyl diradical inwhich one of the hydrogen atoms bonded to a carbon atom, typically aterminal or sp³ carbon atom, is replaced with an heteroaryl group.

[0086] “Leaving group” has the meaning conventionally associated with itin synthetic organic chemistry, i.e., an atom or a group capable ofbeing displaced by a nucleophile and includes halo (such as chloro,bromo and iodo), acyloxy (e.g., acetoxy), mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy),methoxy, N,O-dimethylhydroxylamino and the like.

[0087] “Pharmaceutically acceptable” means approved by a regulatoryagency of the Federal or a state government or listed in the U.S.Pharmacopeia or other generally recognized pharmacopeia for use inanimals, and more particularly in humans.

[0088] “Pharmaceutically acceptable salt” refers to a salt of a compoundof the invention that is pharmaceutically acceptable and that possessesthe desired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

[0089] “Pharmaceutically acceptable vehicle” refers to a diluent,adjuvant, excipient or carrier with which a compound of the invention isadministered.

[0090] “Patient” is a mammal, e.g., a human, mouse, rat, guinea pig,dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

[0091] “Preventing” or “prevention” refers to a reduction in risk ofacquiring a disease or disorder (i.e., causing at least one of theclinical symptoms of the disease not to develop in a patient that may beexposed to or predisposed to the disease but does not yet experience ordisplay symptoms of the disease).

[0092] “Prodrug” refers to a derivative of a drug molecule that requiresa transformation within the body to release the active drug. Prodrugsare frequently (though not necessarily) pharmacologically inactive untilconverted to the parent drug. Typically, prodrugs are designed toovercome pharmaceutical and/or pharmacokinetically based problemsassociated with the parent drug molecule that would otherwise limit theclinical usefulness of the drug.

[0093] “Promoiety” refers to a form of protecting group that when usedto mask a functional group within a drug molecule converts the drug intoa prodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.Ideally, the promoiety is rapidly cleared from the body upon cleavagefrom the prodrug.

[0094] “Protecting group” refers to a grouping of atoms that whenattached to a reactive group in a molecule masks, reduces or preventsthat reactivity. Examples of protecting groups can be found in Green etal., “Protective Groups in Organic Chemistry” , (Wiley, 2^(nd) ed. 1991)and Harrison et al., “Compendium of Synthetic Organic Methods”, Vols.1-8 (John Wiley and Sons, 1971-1996). Representative amino protectinggroups include, but are not limited to, formyl, acetyl, trifluoroacetyl,benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”),trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityland substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxy protecting groups include,but are not limited to, those where the hydroxy group is either acylatedor alkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

[0095] “Substituted” refers to a group in which one or more hydrogenatoms are each independently replaced with the same or differentsubstituent(s). Typical substituents include, but are not limited to,—X, —R²⁹,—O⁻, ═O, —OR²⁹, —SR²⁹,—S⁻, ═S, —NR²⁹R³⁰, ═NR²⁹ , —CX₃, —CF₃,—CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂R²⁹,—OS(O₂)O⁻, —OS(O)₂R²⁹, —P(O)(O⁻)₂, —P(O)(OR²⁹)(O⁻), —OP(O)(OR²⁹)(OR³⁰),—C(O)R²⁹, —C(S)R²⁹, —C(O)OR²⁹, —C(O)NR²⁹R³⁰, —C(O)O⁻, —C(S)OR²⁹,—NR³¹C(O)NR²⁹R³⁰, —NR³¹C(S)NR²⁹R³⁰, —NR³¹C(NR²⁹)NR²⁹R³⁰ and—C(NR²⁹)NR²⁹R³⁰, where each X is independently a halogen; each R²⁹ andR³⁰ are independently hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,cycloheteroalkyldiyl, substituted cycloheteroalkyldiyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, —NR³¹R³², —C(O)R³¹ or—S(O)₂R³¹ or optionally R²⁹ and R³⁰ together with the atom to which theyare both attached form a cycloheteroalkyl or substitutedcycloheteroalkyl ring; and R³¹ and R³² are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl.

[0096] “Treating” or “treatment” of any disease or disorder refers, inone embodiment, to ameliorating the disease or disorder (i.e., arrestingor reducing the development of the disease or at least one of theclinical symptoms thereof). In another embodiment “treating” or“treatment” refers to ameliorating at least one physical parameter,which may not be discernible by the patient. In yet another embodiment,“treating” or “treatment” refers to inhibiting the disease or disorder,either physically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

[0097] “Therapeutically effective amount” means the amount of a compoundthat, when administered to a patient for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the patientto be treated.

[0098] Reference will now be made in detail to preferred embodiments ofthe invention. While the invention will be described in conjunction withthe preferred embodiments, it will be understood that it is not intendedto limit the invention to those preferred embodiments. To the contrary,it is intended to cover alternatives, modifications, and equivalents asmay be included within the spirit and scope of the invention as definedby the appended claims.

4.2 The Compounds of the Invention

[0099] Those of skill in the art will appreciate that compounds ofFormulae (I)-(X), below, share certain structural features in common.These compounds are all GABA analogs (i.e., γ-aminobutryic acidderivatives) to which promoieties have been attached. In particular, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁴⁷, R⁴⁸ and Y are common substituents found incompounds of Formulae (I)-(X).

[0100] The compounds of the invention include compounds of structuralFormula (I):

[0101] or a pharmaceutically acceptable salt, hydrate or solvatethereof, wherein:

[0102] n is 0 or 1;

[0103] Y is 0 or S;

[0104] X is alkyldiyl, substituted alkyldiyl, arylalkyldiyl, substitutedarylalkyldiyl, aryldiyl, substituted aryldiyl, cycloheteroalkyldiyl,substituted cycloheteroalkyldiyl, heteroaryldiyl, substitutedheteroaryldiyl, heteroarylalkyldiyl, substituted heteroarylalkyldiyl,heteroalkyldiyl or substituted heteroalkyldiyl;

[0105] R⁴⁷ is hydrogen, alkyl, substituted alkyl, arylalkyl orsubstituted arylalkyl;

[0106] R² is hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, acyl, substituted acyl, acylamino, substituted acylamino,alkylamino, substituted alkylamino, alklysulfinyl, substitutedalkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio,substituted alkylthio, alkoxycarbonyl, substituted alkylthio, aryl,substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substitutedaryloxy, carbamoyl, substituted carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, substituted dialkylamino, halo, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy,heteroaryloxy, substituted heteroaryloxy, or optionally, R⁴⁷ and R²taken together are alkyldiyl or substituted alkyldiyl;

[0107] R³ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl and substituted heteroarylalkyl;

[0108] R⁴ and R⁵ are independently hydrogen, alkyl, substituted alkyl,acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl or optionally, R⁴ and R⁵taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl,substituted heteroalkyldiyl, or together with the carbon atom to whichthey are attached form a bridged cycloalkyl ring;

[0109] R⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; and

[0110] R⁴⁸ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl.

[0111] Preferably, X is alkyldiyl, substituted alkyldiyl, aryldiyl,substituted aryldiyl, cycloheteroalkyldiyl, substitutedcycloheteroalkyldiyl, heteroaryldiyl, substituted heteroaryldiyl,heteroalkyldiyl or substituted heteroalkyldiyl. More preferably, X isalkyldiyl, substituted alkyldiyl, cycloheteroalkyldiyl, substitutedcycloheteroalkyldiyl, heteroaryldiyl, heteroalkyldiyl or substitutedheteroalkyldiyl. Even more preferably, X is alkyldiyl or substitutedalkyldiyl. Most preferably, X is alkyleno or substituted alkyleno.

[0112] Illustrative embodiments of Formula (I) include Compound 44,Compound 47, and Compound 53 as set forth below:

[0113] Preferred embodiments of compounds of Formula (I) includecompounds of Formula (II-X):

[0114] In Formula (II) to Formula (X) above, n, Y, R⁴⁷, R², R³, R⁶, R⁴,R⁵, R⁷ and R⁴⁸ are as previously defined. Those of skill in the art willappreciate that in Formulae (II) through (X) that X has been replaced bythe respective diyl fragment shown below:

[0115] R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶ are independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, acyloxy, substituted acyloxy, amino, alkylamino,substituted alkylamino, alklysulfinyl, substituted alkylsulfinyl,alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substitutedalkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy,carbamoyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy and hydroxy;

[0116] or optionally, R⁴⁹ and R⁵⁰, R⁵¹ and R⁵², R⁵³ and R⁵⁴, R⁵⁵ andR⁵³, independently, together with the carbon atom(s) to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

[0117] or optionally R⁴⁹ and R⁵¹, R⁵⁰ and R⁵², R⁴⁹ and R⁵², R⁵¹ and R⁵³independently, together with the carbon atom(s) to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

[0118] or optionally, R⁵² and R⁵⁴, R⁵¹ and R⁵⁴, R⁵² and R⁵³independently, together with the carbon atom(s) to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

[0119] or optionally, R⁵³ and R⁵⁵, R⁵⁴ and R⁵⁶, R⁵³ and R⁵⁶ and R⁵⁴ andR⁵⁵ independently, together with the carbon atom(s) to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

[0120] R⁵⁷ and R⁵⁸ are independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, acylamino, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl and substituted heteroarylalkyl;

[0121] or optionally R⁵⁷ and R⁵⁸ together with the carbon atoms to whichthey are attached form an aryl, substituted aryl, heteroaryl,substituted heteroaryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring.

[0122] In one embodiment of compounds of Formulae (I)-(X), n is 0. Inanother embodiment, n is 1. When n is 1, preferably the α-amino acid isof the L-stereochemical configuration or is glycine.

[0123] In a embodiment of compounds of Formulae (I)-(X), R⁷ is selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,substituted cycloalkanyl, cycloheteroalkanyl and substitutedcycloheteroalkanyl. In another embodiment, Y is O and R⁷ is hydrogen. Instill another embodiment, Y is O and R⁷ is alkanyl, substituted alkanyl,alkenyl, substituted alkenyl, aryl or substituted aryl. Preferably, R⁷is —C(CH₃)═CH₂, —CH₂C(O)N(CH₃)₂, —CH₂C(O)N(CH₂CH₃)₂, or

[0124] where V is O or CH₂.

[0125] In a embodiment of compounds of Formulae (I)-(X), R⁴⁷ is H and R²is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl. Preferably, R² is selected from the groupconsisting of hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkyl and substituted heteroarylalkanyl.

[0126] In another embodiment, R⁴⁷ is H and R² is hydrogen, cycloalkanylor alkanyl. Preferably, R² is hydrogen, methyl, 2-propyl, 2-butyl,isobutyl, t-butyl, cyclopentyl or cyclohexyl.

[0127] In still another embodiment, R⁴⁷ is H and R² is substitutedalkanyl. Preferably, R² is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂.

[0128] In still another embodiment, R⁴⁷ is H and R² is selected from thegroup consisting of aryl, arylalkanyl, substituted arylalkanyl andheteroarylalkanyl. Preferably, R² is phenyl, benzyl, 4-hydroxybenzyl,2-imidazolyl or 2-indolyl.

[0129] In yet another embodiment, R⁴⁷ and R² together with the atoms towhich they are attached form a cycloheteroalkyl or substitutedcycloheteroalkyl ring. Preferably R⁴⁷ and R² together with the atoms towhich they are attached form an azetidine, pyrrolidine or piperidinering.

[0130] In another embodiment of compounds of Formulae (I)-(X), R³ ishydrogen. In still another embodiment, R⁶ is hydrogen. In yet anotherembodiment, R³ and R⁶ are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, cycloalkyl and substituted cycloalkyl. Preferably, R³ and R⁶ areindependently selected from the group consisting of hydrogen andalkanyl. More preferably, R³is hydrogen or alkanyl and R⁶ is hydrogen.

[0131] In still another embodiment of compounds of Formulae (I)-(X), R⁴and R⁵ are independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl and substituted heteroaryl. Preferably, R⁴ and R⁵ areindependently selected from the group consisting of hydrogen, alkanyland substituted alkanyl.

[0132] In still another embodiment of compounds of Formulae (I)-(X), R⁴and R⁵ together with the carbon atom to which they are attached arecycloalkanyl or substituted cycloalkanyl. Preferably, R⁴ and R⁵ togetherwith the carbon atom to which they are attached are cyclobutyl,substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexylor substituted cyclohexyl. In another embodiment, R⁴ and R⁵ togetherwith the carbon atom to which they are attached are cycloheteroalkyl orsubstituted cycloheteroalkyl. In still another embodiment, R⁴ and R⁵together with the carbon atom to which they are attached are bridgedcycloalkyl.

[0133] In still another embodiment of compounds of Formulae (I)-(X), R⁴⁸is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl,substituted cycloalkyl, heteroaryl and substituted heteroaryl.Preferably R⁴⁸ is hydrogen, methyl, ethyl, isopropyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl or phenyl. More preferably R⁴⁸ ishydrogen.

[0134] In still another embodiment of compounds of Formulae (I)-(X),R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶ are independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy,acyl, substituted acyl, acylamino, acyloxy, amino, alkylamino,alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, dialkylamino, halo, heteroalkyl, heteroaryl andhydroxy. Preferably, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶ areindependently hydrogen, methyl, ethyl, phenyl, methoxy, ethoxy, amino,acetamido, benzamido, acetoxy, benzoyloxy or hydroxy.

[0135] In a preferred embodiment, R⁴⁹ and R⁵⁰ are independentlyhydrogen, methyl, ethyl, phenyl, methoxy, ethoxy, amino, acetamido,benzamido, acetoxy, benzoyloxy or hydroxy and R⁵¹, R⁵², R⁵³, R⁵⁵ and R⁵⁶are hydrogen. In another preferred embodiment, R⁴⁹ is hydrogen, methyl,ethyl, phenyl, methoxy, ethoxy, amino, acetamido, benzamido, acetoxy,benzoyloxy or hydroxy and R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶ arehydrogen. In still another preferred embodiment, R⁵⁰ is hydrogen,methyl, ethyl, phenyl, methoxy, ethoxy, amino, acetamido, benzamido,acetoxy, benzoyloxy or hydroxy and R⁴⁹, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶are hydrogen. In another preferred embodiment, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³,R⁵⁴, R⁵⁵ and R⁵⁶ are hydrogen.

[0136] In one embodiment of compounds of Formulae (I), (II), (III) (IV)and (VIII), R⁴⁹ and R⁵¹ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably R⁴⁹ and R⁵¹ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl or a 2,2-disubstituted 1,3-dioxolane ring.

[0137] In one embodiment of compounds of Formulae (I), (II), (III) (IV)and (VIII), R⁵⁰ and R⁵² together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably R⁵⁰ and R⁵² together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl or a 2,2-disubstituted 1,3-dioxolane ring.

[0138] In another embodiment of compounds of Formulae (I), (II), (III)(IV) and (VIII), R⁵⁰ and R⁵¹ together with the carbon atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably, R⁵⁰and R⁵¹ together with the carbon atoms to which they are attached form acyclobutyl, cyclopentyl, cyclohexyl or a 2,2-disubstituted 1,3-dioxolanering.

[0139] In still another embodiment of compounds of Formulae (I), (II),(III) (IV) and (VIII), R⁴⁹ and R⁵² together with the carbon atoms towhich they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably, R⁴⁹and R⁵² together with the carbon atoms to which they are attached form acyclobutyl, cyclopentyl, cyclohexyl or a 2,2-disubstituted 1,3-dioxolanering.

[0140] In one embodiment of compounds of Formulae (III) and (IV), R⁵¹and R⁵³ together with the carbon atoms to which they are attached form acycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring. Preferably, R⁵¹ and R⁵³ together with the carbonatoms to which they are attached form a cyclobutyl, cyclopentyl,cyclohexyl or a 2,2-disubstituted 1,3-dioxolane ring.

[0141] In another embodiment of compounds of Formulae (III) and (IV),R⁵² and R⁵⁴ together with the carbon atoms to which they are attachedform a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵² and R⁵⁴ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl or a 2,2-disubstituted 1,3-dioxolane ring.

[0142] In still another embodiment of compounds of Formulae (III) and(IV), R⁵² and R⁵³ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵² and R⁵³ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl or a 2,2-disubstituted 1,3-dioxolane ring.

[0143] In still another embodiment of compounds of Formulae (III) and(IV), R⁵¹ and R⁵⁴ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵¹ and R⁵⁴ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl or a 2,2-disubstituted 1,3-dioxolane ring.

[0144] In one embodiment of compounds of Formulae (IV) and (X), R⁵³ andR⁵⁵ together with the carbon atoms to which they are attached form acycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring. Preferably, R⁵³ and R⁵⁵ together with the carbonatoms to which they are attached form a cyclobutyl, cyclopentyl,cyclohexyl or a 2,2-disubstituted 1,3-dioxolane ring.

[0145] In another embodiment of compounds of Formulae (IV) and (X), R⁵⁴and R⁵⁶ together with the carbon atoms to which they are attached form acycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring. Preferably, R⁵⁴ and R⁵⁶ together with the carbonatoms to which they are attached form a cyclobutyl, cyclopentyl,cyclohexyl or a 2,2-disubstituted 1,3-dioxolane ring.

[0146] In still another embodiment of compounds of Formulae (IV) and(X), R⁵³ and R⁵⁶ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵³ and R⁵⁶ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl or a 2,2-disubstituted 1,3-dioxolane ring.

[0147] In still another embodiment of compounds of Formulae (IV) and(X), R⁵⁴ and R⁵⁵ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵⁴ and R⁵⁵ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl or a 2,2-disubstituted 1,3-dioxolane ring.

[0148] In one embodiment of compounds of Formulae (V)-(X), R⁵⁷ and R⁵⁸are independently hydrogen, alkyl, substituted alkyl, acylamino, aryl,substituted aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl or substituted heteroaryl.Preferably, R⁵⁷ and R⁵⁸ are independently hydrogen, methyl, ethyl orphenyl. Preferably R⁵⁷ is hydrogen, methyl, ethyl or phenyl and R⁵⁸ ishydrogen or methyl. Preferably R⁵⁸ is hydrogen, methyl, ethyl or phenyland R⁵⁷ is hydrogen or methyl.

[0149] In another embodiment of compounds of Formulae (V)-(X), R⁵⁷ andR⁵⁸ together with the carbon atoms to which they are attached form anaryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkylor substituted cycloalkyl ring. Preferably R⁵⁷ and R⁵⁸ together with thecarbon atoms to which they are attached form a cyclopentenyl,cyclohexenyl, phenyl, furyl, thienyl, pyrrolyl, benzothienyl,benzofuryl, indolyl, pyridyl, quinolyl, imidazolyl or oxazolyl ring.More preferably R⁵⁷ and R⁵⁸ together with the carbon atoms to which theyare attached form a phenyl ring.

[0150] In another embodiment of compounds of Formulae (I)-(X), Y is O,R³, R⁶ and R⁷ are hydrogen and R⁴ and R⁵ together with the carbon atomto which they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, bridged cycloalkyl orsubstituted bridged cycloalkyl ring.

[0151] In a preferred embodiment, R⁴ and R⁵ together with the carbonatom to which they are attached form a cycloalkyl or substitutedcycloalkyl ring. Preferably, n is 0. Preferably, n is 1, R⁴⁷ ishydrogen, and R² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl,t-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl,2-imidazolyl, 2-indolyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ 0r—CH₂CH₂CH₂NHC(NH)NH₂. Preferably, n is 1 and R⁴⁷ and R² together withthe atoms to which they are attached form a pyrrolidine ring.

[0152] In another preferred embodiment, R⁴ and R⁵ together with thecarbon atom to which they are attached form a cyclobutyl or substitutedcyclobutyl ring. Preferably, the substituted cyclobutyl ring issubstituted with one or more substituents selected from the groupconsisting of alkanyl, substituted alkanyl, halo, hydroxy, carboxy andalkoxycarbonyl.

[0153] In still another preferred embodiment, R⁴ and R⁵ together withthe carbon atom to which they are attached form a cyclopentyl orsubstituted cyclopentyl ring. Preferably, the cyclopentyl ring issubstituted with one or more substituents selected from the groupconsisting of alkanyl, substituted alkanyl, halo, hydroxy, carboxy oralkoxycarbonyl. More preferably, the cyclopentyl ring is substitutedwith alkanyl. Even more preferably, the cyclopentyl ring is selectedfrom the group consisting of

[0154] Preferably, in this embodiment, R⁷ is hydrogen.

[0155] In still another embodiment, R⁴ and R⁵ together with the carbonatom to which they are attached form a cyclohexyl or substitutedcyclohexyl ring. Preferably, the cyclohexyl ring is substituted with oneor more substituents selected from the group consisting of alkanyl,substituted alkanyl, halo, hydroxy, carboxy or alkoxycarbonyl. Morepreferably, the cyclohexyl ring is substituted with alkanyl. Even morepreferably, the cyclohexyl ring is selected from the group consisting of

[0156] Preferably, in this embodiment, R⁷ is hydrogen.

[0157] In still another embodiment of compounds of Formulae (I)-(X), R⁴and R⁵ together with the carbon atom to which they are attached form acycloheteroalkyl or substituted cycloheteroalkyl ring. In oneembodiment, n is 0. In another embodiment, n is 1, R⁴⁷ is hydrogen, andR² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl,cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl,2-indolyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂,—CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂. In still another embodiment, n is 1 and R⁴⁷ and R²together with the atoms to which they are attached form a pyrrolidinering.

[0158] Preferably, R⁴ and R⁵ together with the carbon atom to which theyare attached form a cycloheteroalkanyl ring. More preferably, thecycloheteroalkanyl ring is selected from the group consisting of

[0159] wherein Z is O, S(O)_(p) or NR¹⁸;

[0160] p is0, 1 or2; and

[0161] R¹⁸ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, acyl and alkoxycarbonyl.

[0162] More preferably, the cycloheteroalkanyl ring is selected from thegroup consisting of

[0163] Preferably, in this embodiment, R⁷ is hydrogen.

[0164] In still another embodiment of compounds of Formulae (I)-(X), R⁴and R⁵ together with the carbon atom to which they are attached form abridged cycloalkyl ring. In one embodiment, n is 0. In anotherembodiment, n is 1, R⁴⁷ is hydrogen, and R² is hydrogen, methyl,2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl,benzyl, 4-hydroxybenzyl, 2-imidazolyl, 2-indolyl, —CH₂OH, —CH(OH)CH₃,—CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In another embodiment, n is 1 andR⁴⁷ and R² together with the atoms to which they are attached form apyrrolidine ring. Preferably, the bridged cycloalkyl group is

[0165] Preferably, in this embodiment, R⁷is hydrogen.

[0166] In still another embodiment of compounds of Formulae (I)-(X), Yis O, R⁶ and R⁷ are hydrogen, R⁴is alkyl, aryl, or cycloalkyl, R⁵ ishydrogen or alkyl and R³ is hydrogen or alkyl. In one embodiment, n is0. In another embodiment, n is 1, R⁴⁷ is hydrogen, and R² is hydrogen,methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl,phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl, 2-indolyl, —CH₂OH,—CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃,—CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In another embodiment, nis 1 and R⁴⁷ and R² together with the atoms to which they are attachedform a pyrrolidine ring. Preferably, R⁴ is phenyl or cycloalkyl, R⁵ishydrogen or methyl and R³ is hydrogen or methyl or R³ is hydrogen, R⁴ isisobutyl and R⁵is hydrogen.

[0167] In still another embodiment of compounds of Formulae (I)-(X), Yis O, R³, R⁵, R⁶ and R⁷ are hydrogen and R⁴ is substituted aryl. In oneembodiment, n is 0. In another embodiment, n is 1, R⁴⁷ is hydrogen, andR² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl,cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl,2-indolyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂,—CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂. In another embodiment, n is 1 and R⁴⁷ and R²together with the atoms to which they are attached form a pyrrolidinering. Preferably, R⁴ is 4-chlorophenyl.

[0168] In still another embodiment of compounds of Formulae (I)-(X), Yis O, R⁵ and R⁷ are hydrogen or alkanyl, R³ and R⁶ are hydrogen and R⁴is substituted heteroalkyl. Preferably, R⁴ is

[0169] A is NR¹⁹, O or S;

[0170] B is alkyl, substituted alkyl, alkoxy, halogen, hydroxy, carboxy,alkoxycarbonyl or amino;

[0171] R¹⁹ is hydrogen, alkyl, cycloalkyl or aryl;

[0172] j is an integer from 0 to 4;

[0173] k is an integer from 1 to 4; and

[0174] 1 is an integer from 0 to 3.

[0175] More preferably, k is 1.

[0176] In still another embodiment of compounds of Formulae (I)-(X), Yis O, R⁵ and R⁷ are hydrogen or alkanyl, R³ and R⁶ are hydrogen and R⁴is substituted alkanyl, cycloalkanyl or substituted cycloalkanyl.Preferably, R⁴ is selected from the group consisting of

[0177] Preferably, R⁴ is

[0178] h is an integer from 1 to 6; and

[0179] i is an integer from 0 to 6.

[0180] More preferably, h is 1, 2, 3 or 4 and i is 0 or 1. Even morepreferably, R⁴ is selected from the group consisting of

[0181] In a preferred embodiment, the compounds of Formula (II) have thestructures of Formulae (XI) and (XII):

[0182] In a preferred embodiment of compounds of Formulae (XI) and(XII), R⁷ is hydrogen. In another embodiment of compounds of Formulae(XI) and (XII), n is 0. In still another embodiment of compounds ofFormulae (XI) and (XII), n is 1, R⁴⁷ is hydrogen and R² is hydrogen,methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl,phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl, 2-indolyl, —CH₂OH,—CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃,—CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In still anotherembodiment, n is 1 and R⁴⁷ and R² together with the atoms to which theyare attached form a pyrrolidine ring.

[0183] In another embodiment of compounds of Formulae (XI) and (XII),R⁴⁸ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, heteroaryl and substitutedheteroaryl. Preferably R⁴⁸ is hydrogen, methyl, ethyl, isopropyl,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or phenyl. Morepreferably R⁴⁸ is hydrogen.

[0184] In still another embodiment of compounds of Formulae (XI) and(XII), R⁴⁹, R⁵⁰, R⁵¹ and R⁵² are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, acyl,substituted acyl, acylamino, acyloxy, amino, alkylamino, alkoxycarbonyl,aryl, substituted aryl, arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, halo, heteroalkyl, heteroaryl and hydroxy. Preferably R⁴⁹,R⁵⁰, R⁵¹ and R⁵² are independently hydrogen, methyl, ethyl, phenyl,methoxy, ethoxy, amino, acetamido, benzamido, acetoxy, benzoyloxy orhydroxy.

[0185] In a preferred embodiment, R⁴⁹ and R⁵⁰ are independentlyhydrogen, methyl, ethyl, phenyl, methoxy, ethoxy, amino, acetamido,benzamido, acetoxy, benzoyloxy or hydroxy and R⁵¹ and R⁵² are hydrogen.In another preferred embodiment, R⁴⁹ is hydrogen, methyl, ethyl, phenyl,methoxy, ethoxy, amino, acetamido, benzamido, acetoxy, benzoyloxy orhydroxy and R⁵⁰, R⁵¹ and R⁵² are hydrogen. In still another preferredembodiment, R⁵⁰ is hydrogen, methyl, ethyl, phenyl, methoxy, ethoxy,amino, acetamido, benzamido, acetoxy, benzoyloxy or hydroxy and R⁴⁹, R⁵¹and R⁵² are hydrogen. In still another preferred embodiment, R⁴⁹, R⁵⁰,R⁵¹ and R⁵² are hydrogen.

[0186] In still another embodiment of compounds of Formulae (XI) and(XII), R⁴⁹ and R⁵¹ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably R⁴⁹ and R⁵¹ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁵⁰ and R⁵² are each hydrogen.I

[0187] In still another embodiment of compounds of Formulae (XI) and(XII), R⁵⁰ and R⁵² together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably R⁵⁰ and R⁵² together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁴⁹ and R⁵¹ are hydrogen.

[0188] In still another embodiment of compounds of Formulae (XI) and(XII), R⁵⁰ and R⁵¹ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably R⁵⁰ and R⁵¹ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring, and R⁴⁹ and R⁵² are hydrogen.

[0189] In still another embodiment of compounds of Formulae (XI) and(XII), R⁴⁹ and R⁵² together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably R⁴⁹ and R⁵² together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring, and R⁵⁰ and R⁵¹ are eachhydrogen.

[0190] In a preferred embodiment, compounds of Formula (III) have thestructures of Formulae (XIII) and (XIV):

[0191] In a preferred embodiment of compounds of Formulae (XIII) and(XIV), R⁷ is hydrogen. In another preferred embodiment of compounds ofFormulae (XIII) and (XIV), n is 0. In still another embodiment ofcompounds of Formulae (XIII) and (XIV), n is 1, R⁴⁷ is hydrogen and R ishydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl,cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl, 2-indolyl,—CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂,—CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In stillanother embodiment, n is 1 and R⁴⁷ and R² together with the atoms towhich they are attached form a pyrrolidine ring.

[0192] In one embodiment of compounds of Formulae (XIII) and (XIV), R⁴⁸is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl,substituted cycloalkyl, heteroaryl and substituted heteroaryl.Preferably R⁴⁸ is hydrogen, methyl, ethyl, isopropyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl or phenyl. More preferably R⁴⁸ ishydrogen.

[0193] In one embodiment of compounds of Formulae (XIII) and (XIV), R⁴⁹,R⁵⁰, R⁵¹, R⁵², R⁵³ and R⁵⁴ are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, acyl,substituted acyl, acylamino, acyloxy, amino, alkylamino, alkoxycarbonyl,aryl, substituted aryl, arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, halo, heteroalkyl, heteroaryl and hydroxy. Preferably R⁴⁹,R⁵⁰, R⁵¹, R⁵², R⁵³ and R⁵⁴ are independently hydrogen, methyl, ethyl,phenyl, methoxy, ethoxy, amino, acetamido, benzamido, acetoxy,benzoyloxy or hydroxy.

[0194] In a preferred embodiment, R⁴⁹ and R⁵⁰ are independentlyhydrogen, methyl, ethyl, phenyl, methoxy, ethoxy, amino, acetamido,benzamido, acetoxy, benzoyloxy or hydroxy and R⁵¹, R⁵², R⁵³ and R⁵⁴ arehydrogen. In another preferred embodiment R⁴⁹ is hydrogen, methyl,ethyl, phenyl, methoxy, ethoxy, amino, acetamido, benzamido, acetoxy,benzoyloxy or hydroxy and R⁵⁰, R⁵¹, R⁵², R⁵³ and R⁵⁴ are hydrogen. Instill another preferred embodiment, R⁵⁰ is hydrogen, methyl, ethyl,phenyl, methoxy, ethoxy, amino, acetamido, benzamido, acetoxy,benzoyloxy or hydroxy and R⁴⁹, R⁵¹, R⁵², R⁵³ and R⁵⁴ are hydrogen. Instill another preferred embodiment, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³ and R⁵⁴ arehydrogen.

[0195] In still another embodiment of compounds of Formulae (XIII) and(XIV), R⁴⁹ and R⁵¹ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁴⁹ and R⁵¹ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁵⁰, R⁵², R⁵³ and R⁵⁴ arehydrogen.

[0196] In still another embodiment of compounds of Formulae (XIII) and(XIV), R⁵⁰ and R⁵² together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵⁰ and R⁵² together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁴⁹, R⁵¹, R⁵³ and R⁵⁴ arehydrogen.

[0197] In still another embodiment of compounds of Formulae (XIII) and(XIV), R⁵⁰ and R⁵¹ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵⁰ and R⁵¹ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁴⁹, R⁵², R⁵³ and R⁵⁴ arehydrogen.

[0198] In still another embodiment of compounds of Formulae (XIII) and(XIV), R⁴⁹ and R⁵² together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁴⁹ and R⁵² together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentanethylene-1,3-dioxolane ring and R⁵⁰, R⁵¹, R⁵³ and R⁵⁴ are eachhydrogen.

[0199] In still another embodiment of compounds of Formulae (XIII) and(XIV), R⁵¹ and R⁵³ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵¹ and R⁵³ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁴⁹, R⁵⁰, R⁵² and R⁵⁴ arehydrogen.

[0200] In still another embodiment of compounds of Formulae (XIII) and(XIV), R⁵² and R⁵⁴ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵² and R⁵⁴ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁴⁹, R⁵⁰, R⁵¹ and R⁵³ are eachhydrogen.

[0201] In still another embodiment of compounds of Formulae (XIII) and(XIV), R⁵² and R⁵³ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵² and R⁵³ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁴⁹, R⁵⁰, R⁵¹ and R⁵⁴ are eachhydrogen.

[0202] In still another embodiment of compounds of Formulae (XIII) and(XIV), R⁵¹ and R⁵⁴ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵¹ and R⁵⁴ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁴⁹, R⁵⁰, R⁵² and R⁵³ arehydrogen.

[0203] In a preferred embodiment, the compounds of Formula (IV) have thestructures of Formulae (XV) and (XVI):

[0204] In a preferred embodiment of compounds of Formulae (XV) and(XVI), R⁷ is hydrogen. In another preferred embodiment of compounds ofFormulae (XV) and (XVI), n is 0. In still another embodiment ofcompounds of Formulae (XV) and (XVI), n is 1, R⁴⁷ is hydrogen and R² ishydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl,cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl, 2-indolyl,—CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂,—CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In anotherembodiment, n is 1 and R⁴⁷ and R² together with the atoms to which theyare attached form a pyrrolidine ring.

[0205] In an embodiment of compounds of Formulae (XV) and (XVI), R⁴⁸ isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl,substituted cycloalkyl, heteroaryl and substituted heteroaryl.Preferably R⁴⁸ is hydrogen, methyl, ethyl, isopropyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl or phenyl. More preferably R⁴⁸ ishydrogen.

[0206] In another embodiment of compounds of Formulae (XV) and (XVI),R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶ are independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy,acyl, substituted acyl, acylamino, acyloxy, amino, alkylamino,alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, dialkylamino, halo, heteroalkyl, heteroaryl andhydroxy. Preferably R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶ areindependently hydrogen, methyl, ethyl, phenyl, methoxy, ethoxy, amino,acetamido, benzamido, acetoxy, benzoyloxy or hydroxy.

[0207] In a preferred embodiment, R⁴⁹ and R⁵⁰ are independentlyhydrogen, methyl, ethyl, phenyl, methoxy, ethoxy, amino, acetamido,benzamido, acetoxy, benzoyloxy or hydroxy and R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵and R⁵⁶ are hydrogen. In another preferred embodiment, R⁴⁹ is hydrogen,methyl, ethyl, phenyl, methoxy, ethoxy, amino, acetamido, benzamido,acetoxy, benzoyloxy or hydroxy, and R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶are hydrogen. In still another preferred embodiment, R⁵⁰ is hydrogen,methyl, ethyl, phenyl, methoxy, ethoxy, amino, acetamido, benzamido,acetoxy, benzoyloxy or hydroxy and R⁴⁹, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶are hydrogen. In still another preferred embodiment R⁴⁹, R⁵⁰, R⁵¹, R⁵²,R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶ are hydrogen.

[0208] In still another embodiment of compounds of Formulae (XV) and(XVI), R⁴⁹ and R⁵¹ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁴⁹ and R⁵¹ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁵⁰, R⁵², R⁵³, R⁵⁴, R⁵⁵ andR⁵⁶ are hydrogen.

[0209] In still another embodiment of compounds of Formulae (XV) and(XVI), R⁵⁰ and R⁵² together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵⁰ and R⁵² together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁴⁹, R⁵¹, R⁵³, R⁵⁴, R⁵⁵ andR⁵⁶ are hydrogen.

[0210] In still another embodiment of compounds of Formulae (XV) and(XVI), R⁵⁰ and R⁵¹ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵⁰ and R⁵¹ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁴⁹, R⁵², R⁵³, R⁵⁴, R⁵⁵ andR⁵⁶ are hydrogen.

[0211] In still another embodiment of compounds of Formulae (XV) and(XVI), R⁴⁹ and R⁵² together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁴⁹ and R⁵² together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁵⁰, R⁵¹, R⁵³, R⁵⁴, R⁵⁵ andR⁵⁶ are hydrogen.

[0212] In still another embodiment of compounds of Formulae (XV) and(XVI), R⁵¹ and R⁵³ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵¹ and R⁵³ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring, and R⁴⁹, R⁵⁰, R⁵², R⁵⁴, R⁵⁵ andR⁵⁶ are hydrogen.

[0213] In still another embodiment, of compounds of Formulae (XV) and(XVI), R⁵² and R⁵⁴ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵² and R⁵⁴ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁴⁹, R⁵⁰, R⁵¹, R⁵³, R⁵⁵ andR⁵⁶ are each hydrogen.

[0214] In still another embodiment of compounds of Formulae (XV) and(XVI), R⁵² and R⁵³ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵² and R⁵³ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-penetamethylene-1,3-dioxolane ring and R⁴⁹, R⁵⁰, R⁵¹, R⁵⁴, R⁵⁵ andR⁵⁶ are hydrogen.

[0215] In still another embodiment of compounds of Formulae (XV) and(XVI), R⁵¹ and R⁵⁴ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵¹ and R⁵⁴ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁴⁹, R⁵⁰, R⁵², R⁵³, R⁵⁵ andR⁵⁶ are hydrogen.

[0216] In still another embodiment of compounds of Formulae (XV) and(XVI), R⁵³ and R⁵⁵ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵³ and R⁵⁵ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵⁴ andR⁵⁶ are each hydrogen.

[0217] In still another embodiment of compounds of Formulae (XV) and(XVI), R⁵⁴ and R⁵⁶ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵⁴ and R⁵⁶ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring and R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³ andR⁵⁵ are each hydrogen.

[0218] In still another embodiment of compounds of Formulae (XV) and(XVI), R⁵⁴ and R⁵⁵ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵⁴ and R⁵⁵ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring, and R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³ andR⁵⁶ are each hydrogen.

[0219] In still another embodiment of compounds of Formulae (XV) and(XVI), R⁵³ and R⁵⁶ together with the carbon atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R⁵³ and R⁵⁶ together withthe carbon atoms to which they are attached form a cyclobutyl,cyclopentyl, cyclohexyl, 2,2-dimethyl-1,3-dioxolane or2,2-pentamethylene-1,3-dioxolane ring, and R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵⁴ andR⁵⁵ are each hydrogen.

[0220] In a preferred embodiment, the compounds of Formula (V) have thestructures of Formulae (XVII) and (XVIII):

[0221] In a preferred embodiment of compounds of Formulae (XVII) and(XVIII), R⁷ is hydrogen. In another preferred embodiment of compounds ofFormulae (XVII) and (XVIII), n is 0. In still another embodiment ofcompounds of Formulae (XVII) and (XVIII), n is 1, R⁴⁷ is hydrogen and R²is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl,cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl, 2-indolyl,—CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂,—CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In stillanother embodiment, n is 1 and R⁴⁷ and R² together with the atoms towhich they are attached form a pyrrolidine ring.

[0222] In a embodiment of compounds of Formulae (XVII) and (XVIII), R⁴⁸is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl,substituted cycloalkyl, heteroaryl and substituted heteroaryl.Preferably R⁴⁸ is hydrogen, methyl, ethyl, isopropyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl or phenyl. More preferably R⁴⁸ ishydrogen.

[0223] In another embodiment of compounds of Formulae (XVII) and(XVIII), R⁵⁷ and R⁵⁸ are independently hydrogen, alkyl, substitutedalkyl, acylamino, aryl, substituted aryl, arylalkyl, cycloalkyl,cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl orsubstituted heteroaryl. Preferably, R⁵⁷ and R⁵⁸ are independentlyhydrogen, methyl, ethyl or phenyl. Preferably R⁵⁷ is hydrogen, methyl,ethyl or phenyl and R⁵⁸ is hydrogen or methyl. Preferably R⁵⁸ isselected from the group consisting of hydrogen, methyl, ethyl or phenyland R⁵⁷ is hydrogen or methyl.

[0224] In still another embodiment of compounds of Formulae (XVII) and(XVIII), R⁵⁷ and R⁵⁸ together with the carbon atoms to which they areattached form an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, cycloalkyl or substituted cycloalkyl ring. Preferably, R⁵⁷and R⁵⁸ together with the carbon atoms to which they are attached form acyclopentenyl, cyclohexenyl, phenyl, furyl, thienyl, pyrrolyl,benzothienyl, benzofuryl, indolyl, pyridyl, quinolyl, imidazolyl oroxazolyl ring. More preferably, R⁵⁷ and R⁵⁸ together with the carbonatoms to which they are attached form a phenyl ring.

[0225] In a preferred embodiment, compounds of Formula (VI) have thestructures of Formulae (XIX) and (XX):

[0226] In a preferred embodiment of compounds of Formulae (XIX) and(XX), R⁷ is hydrogen. In another preferred embodiment of compounds ofFormulae (XIX) and (XX), n is 0. In still another preferred embodiment,of compounds of Formulae (XIX) and (XX), n is 1, R⁴⁷ is hydrogen and R²is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl,cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl, 2-indolyl,—CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂,—CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In stillanother embodiment, n is 1 and R⁴⁷ and R² together with the atoms towhich they are attached form a pyrrolidine ring.

[0227] In one embodiment of compounds of Formulae (XIX) and (XX), R⁴⁸ isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl,substituted cycloalkyl, heteroaryl and substituted heteroaryl.Preferably R⁴⁸ is hydrogen, methyl, ethyl, isopropyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl or phenyl. More preferably R⁴⁸ ishydrogen.

[0228] In another embodiment of compounds of Formulae (XIX) and (XX),R⁴⁹ and R⁵⁰ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, acyl, substituted acyl,acylamino, acyloxy, amino, alkylamino, alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, halo,heteroalkyl, heteroaryl and hydroxy and R⁵⁷ and R⁵⁸ are independentlyhydrogen, alkyl, substituted alkyl, acylamino, aryl, substituted aryl,arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl or substituted heteroaryl. Preferably, R⁴⁹ andR⁵⁰ are independently hydrogen, methyl, ethyl, phenyl, methoxy, ethoxy,amino, acetamido, benzamido, acetoxy, benzoyloxy or hydroxy and R⁵⁷ andR⁵⁸ are independently hydrogen, methyl, ethyl or phenyl.

[0229] In a preferred embodiment, R⁴⁹ and R⁵⁰ are hydrogen, methyl,ethyl, phenyl, methoxy, ethoxy, amino, acetamido, benzamido, acetoxy,benzoyloxy or hydroxy and R⁵⁷ and R⁵⁸ are hydrogen. In another preferredembodiment, R⁴⁹ is hydrogen, methyl, ethyl, phenyl, methoxy, ethoxy,amino, acetamido, benzamido, acetoxy, benzoyloxy or hydroxy and R⁵⁰, R⁵⁷and R⁵⁸ are hydrogen. In still another preferred embodiment R⁵⁰ ishydrogen, methyl, ethyl, phenyl, methoxy, ethoxy, amino, acetamido,benzamido, acetoxy, benzoyloxy or hydroxy and R⁴⁹, R⁵⁷ and R⁵⁸ arehydrogen. In another preferred embodiment R⁴⁹, R⁵⁰, R⁵⁷ and R⁵⁸ arehydrogen.

[0230] In yet another preferred embodiment of compounds of Formulae(XIX) and (XX), R⁴⁹ and R⁵⁰ are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, acyl,substituted acyl, acylamino, acyloxy, amino, alkylamino, alkoxycarbonyl,aryl, substituted aryl, arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, 30 halo, heteroalkyl, heteroaryl and hydroxy and R⁵⁷ andR⁵⁸ together with the carbon atoms to which they are attached form anaryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkylor substituted cycloalkyl ring. Preferably, R⁴⁹ and R⁵⁰ areindependently hydrogen or methyl and R⁵⁷ and R⁵⁸ together with thecarbon atoms to which they are attached form a cyclopentenyl,cyclohexenyl, phenyl, furyl, thienyl, pyrrolyl, benzothienyl,benzofuryl, indolyl, pyridyl, quinolyl, imidazolyl or oxazolyl ring.More preferably, R⁴⁹ and R⁵⁰ are independently hydrogen or methyl andR⁵⁷ and R⁵⁸ together with the carbon atoms to which they are attachedform a phenyl ring. Most preferably, R⁴⁹ and R⁵⁰ are hydrogen, and R⁵⁷and R⁵⁸ together with the carbon atoms to which they are attached form aphenyl ring.

[0231] In a preferred embodiment, the compounds of Formula (VII) havethe structures of Formulae (XXI) and (XXII):

[0232] In a preferred embodiment of compounds of Formulae (XXI) and(XXII), R⁷ is hydrogen. In another preferred embodiment of compounds ofFormulae (XXI) and (XXII), n is 0. In still another embodiment ofcompounds of Formulae (XXI) and (XXII), n is 1, R⁴⁷ is hydrogen and R²is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl,cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl, 2-indolyl,—CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂,—CH₂CH₂SCH₃, —H₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In stillanother embodiment, n is 1 and R⁴⁷ and R² together with the atoms towhich they are attached form a pyrrolidine ring.

[0233] In one embodiment of compounds of Formulae (XXI) and (XXII), R⁴⁸is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl,substituted cycloalkyl, heteroaryl and substituted heteroaryl.Preferably R⁴⁸ is hydrogen, methyl, ethyl, isopropyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl or phenyl. More preferably, R⁴⁸ ishydrogen.

[0234] In another embodiment of compounds of Formulae (XXI) and (XXII),R⁵³ and R⁵⁴ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, acyl, substituted acyl,acylamino, acyloxy, amino, alkylamino, alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, halo,heteroalkyl, heteroaryl and hydroxy and R⁵⁷ and R⁵⁸ are independentlyhydrogen, alkyl, substituted alkyl, acylamino, aryl, substituted aryl,arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl or substituted heteroaryl. Preferably R⁵³ andR⁵⁴ are independently hydrogen, methyl, ethyl, phenyl, methoxy, ethoxy,amino, acetamido, benzamido, acetoxy, benzoyloxy or hydroxy and R⁵⁷ andR⁵⁸ are independently hydrogen, methyl, ethyl or phenyl.

[0235] In a preferred embodiment, R⁵³ and R⁵⁴ are independentlyhydrogen, methyl, ethyl, phenyl, methoxy, ethoxy, amino, acetamido,benzamido, acetoxy, benzoyloxy or hydroxy and R⁵⁷ and R⁵⁸ are hydrogen.In another preferred embodiment, R⁵³ is hydrogen, methyl, ethyl, phenyl,methoxy, ethoxy, amino, acetamido, benzamido, acetoxy, benzoyloxy orhydroxy and R⁵⁴, R⁵⁷ and R⁵⁸ are hydrogen. In still another preferredembodiment R⁵⁴ is hydrogen, methyl, ethyl, phenyl, methoxy, ethoxy,amino, acetamido, benzamido, acetoxy, benzoyloxy or hydroxy and R⁵³, R⁵⁷and R⁵⁸ are hydrogen. In still another preferred embodiment, R⁵³, R⁵⁴,R⁵⁷ and R⁵⁸ are hydrogen.

[0236] In yet another preferred embodiment of compounds of Formulae(XXI) and (XXII), R⁵³ and R⁵⁴ are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, acyl,substituted acyl, acylamino, acyloxy, amino, alkylamino, alkoxycarbonyl,aryl, substituted aryl, arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, halo, heteroalkyl, heteroaryl and hydroxy and R⁵⁷ and R⁵⁸together with the carbon atoms to which they are attached form an aryl,substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl orsubstituted cycloalkyl ring. Preferably, R⁵³ and R⁵⁴ are independentlyhydrogen or methyl and R⁵⁷ and R⁵⁸ together with the carbon atoms towhich they are attached form a cyclopentenyl, cyclohexenyl, phenyl,furyl, thienyl, pyrrolyl, benzothienyl, benzofuryl, indolyl, pyridyl,quinolyl, imidazolyl or oxazolyl ring. More preferably, R⁵³ and R⁵⁴ areindependently hydrogen or methyl, and R⁵⁷ and R⁵⁸ together with thecarbon atoms to which they are attached form a phenyl ring. Even morepreferably, R⁵³ and R⁵⁴ are hydrogen, and R⁵⁷ and R⁵⁸ together with thecarbon atoms to which they are attached form a phenyl ring.

[0237] In a preferred embodiment, compounds of Formula (VIII) have thestructures of Formulae (XXIII) and (XXIV):

[0238] In a preferred embodiments of compounds of Formulae (XXIII) and(XXIV), R⁷ is hydrogen. In another preferred embodiment of compounds ofFormulae (XXIII) and (XXIV), n is 0. In still another embodiment ofcompounds of Formulae (XXIII) and (XXIV), n is 1, R⁴⁷ is hydrogen and R²is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl,cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl, 2-indolyl,—CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂,—CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In stillanother embodiment, n is 1 and R⁴⁷ and R² together with the atoms towhich they are attached form a pyrrolidine ring.

[0239] In one embodiment of compounds of Formulae (XXIII) and (XXIV),R⁴⁸ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, heteroaryl and substitutedheteroaryl. Preferably, R⁴⁸ is hydrogen, methyl, ethyl, isopropyl,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or phenyl. Morepreferably, R⁴⁸ is hydrogen.

[0240] In another embodiment of compounds of Formulae (XXIII) and(XXIV), R⁴⁹, R⁵⁰, R⁵¹ and R⁵² are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, acyl,substituted acyl, acylamino, acyloxy, amino, alkylamino, alkoxycarbonyl,aryl, substituted aryl, arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, halo, heteroalkyl, heteroaryl and hydroxy and R⁵⁷ and R⁵⁸are independently hydrogen, alkyl, substituted alkyl, acylamino, aryl,substituted aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl or substituted heteroaryl.Preferably, R⁴⁹, R⁵⁰, R⁵¹ and R⁵² are independently hydrogen, methyl,ethyl, phenyl, methoxy, ethoxy, amino, acetamido, benzamido, acetoxy,benzoyloxy or hydroxy and R⁵⁷ and R⁵⁸ are independently hydrogen,methyl, ethyl or phenyl.

[0241] In a preferred embodiment, R⁴⁹, R⁵⁰, R⁵¹ and R⁵² areindependently hydrogen, methyl, ethyl, phenyl, methoxy, ethoxy, amino,acetamido, benzamido, acetoxy, benzoyloxy or hydroxy and R⁵⁷ and R⁵⁸ arehydrogen. In another preferred embodiment, R⁴⁹ is hydrogen, methyl,ethyl, phenyl, methoxy, ethoxy, amino, acetamido, benzamido, acetoxy,benzoyloxy or hydroxy and R⁵⁰, R⁵¹, R⁵², R⁵⁷ and R⁵⁸ are hydrogen. Instill another preferred embodiment, R⁵⁰ is hydrogen, methyl, ethyl,phenyl, methoxy, ethoxy, amino, acetamido, benzamido, acetoxy,benzoyloxy or hydroxy and R⁴⁹, R⁵¹, R⁵², R⁵⁷ and R⁵⁸ are hydrogen. Instill another preferred embodiment, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵⁷ and R⁵⁸ arehydrogen.

[0242] In yet another preferred embodiment of compounds of Formulae(XXIII) and (XXIV), R⁴⁹, R⁵⁰, R⁵¹ and R⁵² are independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy,acyl, substituted acyl, acylamino, acyloxy, amino, alkylamino,alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, dialkylamino, halo, heteroalkyl, heteroaryl andhydroxy and R⁵⁷ and R⁵⁸ together with the carbon atoms to which they areattached form an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, cycloalkyl or substituted cycloalkyl ring. Preferably, R⁴⁹,R⁵⁰, R⁵¹ and R⁵² are independently hydrogen or methyl, and R⁵⁷ and R⁵⁸together with the carbon atoms to which they are attached form acyclopentenyl, cyclohexenyl, phenyl, furyl, thienyl, pyrrolyl,benzothienyl, benzofuryl, indolyl, pyridyl, quinolyl, imidazolyl oroxazolyl ring. More preferably, R⁴⁹, R⁵⁰, R⁵¹ and R⁵² are independentlyhydrogen or methyl and R57 and R⁵⁸ together with the carbon atoms towhich they are attached form a phenyl ring. Even more preferably, R⁴⁹,R⁵⁰, R⁵¹ and R⁵² are hydrogen, and R⁵⁷ and R⁵⁸ together with the carbonatoms to which they are attached form a phenyl ring.

[0243] In a preferred embodiment, the compounds of Formula (IX) have thestructures of Formulae (XXV) and (XXVI):

[0244] In a preferred embodiment of compounds of Formulae (XXV) and(XXVI), R⁷ is hydrogen. In another preferred embodiment of compounds ofFormulae (XXV) and (XXVI), n is 0. In still another embodiment ofcompounds of Formulae (XXV) and (XXVI), n is 1, R⁴⁷ is hydrogen and R²is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl,cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl, 2-indolyl,—CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂,—CH₂CH₂CONH2,—CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂.In still another embodiment, n is 1 and R⁴⁷ and R² together with theatoms to which they are attached form a pyrrolidine ring.

[0245] In one embodiment of compounds of Formulae (XXV) and (XXVI), R⁴⁸is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl,substituted cycloalkyl, heteroaryl and substituted heteroaryl.Preferably R⁴⁸ is hydrogen, methyl, ethyl, isopropyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl or phenyl. More preferably R⁴⁸ ishydrogen.

[0246] In another embodiment of compounds of Formulae (XXV) and (XXVI),R⁴⁹, R⁵⁰, R⁵⁵ and R⁵⁶ are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, acyl,substituted acyl, acylamino, acyloxy, amino, alkylamino, alkoxycarbonyl,aryl, substituted aryl, arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, halo, heteroalkyl, heteroaryl and hydroxy and R⁵⁷ and R⁵⁸are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, acylamino, aryl, substituted aryl, arylalkyl,cycloalkyl, cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl or substituted heteroaryl. Preferably R⁴⁹, R⁵⁰, R⁵⁵ and R⁵⁶are independently hydrogen, methyl, ethyl, phenyl, methoxy, ethoxy,amino, acetamido, benzamido, acetoxy, benzoyloxy or hydroxy and R⁵⁷ andR⁵⁸ are independently hydrogen, methyl, ethyl or phenyl.

[0247] In a preferred embodiment R⁴⁹, R⁵⁰, R⁵⁵ and R⁵⁶ are independentlyhydrogen, methyl, ethyl, phenyl, methoxy, ethoxy, amino, acetamido,benzamido, acetoxy, benzoyloxy or hydroxy and R⁵⁷ and R⁵⁸ are hydrogen.In another preferred embodiment R⁴⁹ is hydrogen, methyl, ethyl, phenyl,methoxy, ethoxy, amino, acetamido, benzamido, acetoxy, benzoyloxy orhydroxy and R⁵⁰, R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ are hydrogen. In still anotherpreferred embodiment, R⁵⁰ is hydrogen, methyl, ethyl, phenyl, methoxy,ethoxy, amino, acetamido, benzamido, acetoxy, benzoyloxy or hydroxy andR⁴⁹, R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ are hydrogen. In another preferredembodiment, R⁴⁹, R⁵⁰, R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ are hydrogen.

[0248] In yet another preferred embodiment of compounds of Formulae(XXV) and (XXVI), R 49, R⁵⁰, R⁵⁵ and R⁵⁶ are independently selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkoxy,acyl, substituted acyl, acylamino, acyloxy, amino, alkylamino,alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, dialkylamino, halo, heteroalkyl, heteroaryl andhydroxy and R⁵⁷ and R⁵⁸ together with the carbon atoms to which they areattached form an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, cycloalkyl or substituted cycloalkyl ring. Preferably R⁴⁹,R⁵⁰, R⁵⁵ and R⁵⁶ are independently hydrogen or methyl and R⁵⁷ and R⁵⁸together with the carbon atoms to which they are attached form acyclopentenyl, cyclohexenyl, phenyl, furyl, thienyl, pyrrolyl,benzothienyl, benzofuryl, indolyl, pyridyl, quinolyl, imidazolyl oroxazolyl ring. More preferably, R⁴⁹, R⁵⁰, R⁵⁵ and R⁵⁶ are eachindependently hydrogen or methyl and R⁵⁷ and R⁵⁸ together with thecarbon atoms to which they are attached form a phenyl ring. Even morepreferably, R⁴⁹, R⁵⁰, R⁵⁵ and R⁵⁶ are hydrogen, and R⁵⁷ and R⁵⁸ togetherwith the carbon atoms to which they are attached form a phenyl ring.

[0249] In one preferred embodiment, the compounds of Formula (IX) havethe structures of Formulae (XXVII) and (XXVIII):

[0250] In a preferred embodiment of compounds of Formulae (XXVII) and(XXVIII), R⁷ is hydrogen. In another preferred embodiment of compoundsof Formulae (XXVII) and (XXVIII), n is 0. In still another embodiment ofcompounds of Formulae (XXVII) and (XXVIII), n is 1, R⁴⁷ is hydrogen andR² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl,cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl,2-indolyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂,—CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂. In still another embodiment, n is 1 and R⁴⁷ and R²together with the atoms to which they are attached form a pyrrolidinering.

[0251] In one embodiment of compounds of Formulae (XXVII) and (XXVIII),R⁴⁸ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, heteroaryl and substitutedheteroaryl. Preferably, R⁴⁸ is hydrogen, methyl, ethyl, isopropyl,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or phenyl. Morepreferably, R⁴⁸ is hydrogen.

[0252] In one embodiment of compounds of Formulae (XXVII) and (XXVIII),R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶ are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, acyl,substituted acyl, acylamino, acyloxy, amino, alkylamino, alkoxycarbonyl,aryl, substituted aryl, arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, halo, heteroalkyl, heteroaryl and hydroxy and R⁵⁷ and R⁵⁸are independently hydrogen, alkyl, substituted alkyl, acylamino, aryl,substituted aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl or substituted heteroaryl.Preferably, R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶ are independently hydrogen, methyl,ethyl, phenyl, methoxy, ethoxy, amino, acetamido, benzamido, acetoxy,benzoyloxy or hydroxy and R⁵⁷ and R⁵⁸ are independently hydrogen,methyl, ethyl or phenyl.

[0253] In a preferred embodiment, R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶ areindependently hydrogen, methyl, ethyl, phenyl, methoxy, ethoxy, amino,acetamido, benzamido, acetoxy, benzoyloxy or hydroxy and R⁵⁷ and R⁵⁸ arehydrogen. In another preferred embodiment, R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷ andR⁵⁸ are hydrogen.

[0254] In yet another preferred embodiment of compounds of Formulae(XXVII) and (XXVIII), R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶ are independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy,acyl, substituted acyl, acylamino, acyloxy, amino, alkylamino,alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, dialkylamino, halo, heteroalkyl, heteroaryl andhydroxy and R⁵⁷ and R⁵⁸ together with the carbon atoms to which they areattached form an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, cycloalkyl or substituted cycloalkyl ring. Preferably, R⁵³,R⁵⁴, R⁵⁵ and R⁵⁶ are independently hydrogen or methyl and R⁵⁷ and R⁵⁸together with the carbon atoms to which they are attached form acyclopentenyl, cyclohexenyl, phenyl, furyl, thienyl, pyrrolyl,benzothienyl, benzofuryl, indolyl, pyridyl, quinolyl, imidazolyl oroxazolyl ring. More preferably, R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶ are independentlyhydrogen or methyl and R⁵⁷ and R⁵⁸ together with the carbon atoms towhich they are attached form a phenyl ring. Even more preferably, R⁵³,R⁵⁴, R⁵⁵ and R⁵⁶ are hydrogen, and R⁵⁷ and R⁵⁸ together with the carbonatoms to which they are attached form a phenyl ring.

4.3 Synthesis of The Compounds of the Invention

[0255] The compounds of the invention may be obtained via the syntheticmethods illustrated in Schemes 1-11. Those of skill in the art willappreciate that a preferred synthetic route to the compounds of theinvention will consist of attaching promoieties to GABA analogs.Numerous methods have been described in the art for the synthesis ofGABA analogs (See, e.g., Satzinger et al., U.S. Pat. No. 4,024,175;Silverman et al., U.S. Pat. No. 5,563,175; Horwell et al., U.S. Pat. No.6,020,370; Silverman et al., U.S. Pat. No. 6,028,214; Horwell et al.,U.S. Pat. No. 6,103,932; Silverman et al., U.S. Pat. No. 6,117,906;Silverman, International Application No. WO 92/09560; Silverman et al.,International Application No. WO 93/23383; Horwell et al., InternationalApplication No. WO 97/29101, Horwell et al., International ApplicationNo. WO 97/33858; Horwell et al., International Application No. WO97/33859; Bryans et al., International Application No. WO 98/17627;Guglietta et al., International Application No. WO 99/08671; Bryans etal., International Application No. WO 99/21824; Bryans et al.,International Application No. WO 99/31057; Belliotti et al.,International Application No. WO 99/31074; Bryans et al., InternationalApplication No. WO 99/31075; Bryans et al., International ApplicationNo. WO 99/61424; Bryans et al., International Application No. WO00/15611; Bryans, International Application No. WO 00/31020; and Bryanset al., International Application No. WO 00/50027). Other methods areknown in the art for synthesizing GABA analogs, which are readilyaccessible to the skilled artisan. The promoieties described herein, areknown in the art and may be prepared and attached to GABA analogs byestablished procedures (See e.g., Green et al., “Protective Groups inOrganic Chemistry”, (Wiley, 2^(nd) ed. 1991); Harrison et al.,“Compendium of Synthetic Organic Methods”, Vols. 1-8 (John Wiley andSons, 1971-1996); “Beilstein Handbook of Organic Chemistry,” BeilsteinInstitute of Organic Chemistry, Frankfurt, Germany; Feiser et al.,“Reagents for Organic Synthesis,” Volumes 1-17, Wiley Interscience;Trost et al., “Comprehensive Organic Synthesis,” Pergamon Press, 1991;“Theilheimer's Synthetic Methods of Organic Chemistry,” Volumes 1-45,Karger, 1991; March, “Advanced Organic Chemistry,” Wiley Interscience,1991; Larock “Comprehensive Organic Transformations,” VCH Publishers,1989; Paquette, “Encyclopedia of Reagents for Organic Synthesis,” JohnWiley & Sons, 1995, Bodanzsky, “Principles of Peptide Synthesis,”Springer Verlag, 1984; Bodanzsky, “Practice of Peptide Synthesis,”Springer Verlag, 1984).

[0256] Accordingly, starting materials useful for preparing compounds ofthe invention and intermediates thereof are commercially available orcan be prepared by well-known synthetic methods. Other methods forsynthesis of the prodrugs described herein are either described in theart or will be readily apparent to the skilled artisan in view of thereferences provided above and may be used to synthesize the compounds ofthe invention. Accordingly, the methods presented in the Schemes hereinare illustrative rather than comprehensive.

[0257] In any of the Schemes below, after the amino group of a GABAanalog has been functionalized with a promoicty or other protectinggroup, the carboxylic acid group may be converted to an ester orthioester by many synthetic methods, which are well-known to the skilledartisan. In one preferred embodiment, GA13A analogs may be reacted withan alcohol or thiol in the presence of a coupling reagent (e.g.,carbodiimide and dimethylaminopyridine) to provide the ester. In anotherpreferred embodiment, GABA analogs may be reacted with an alkyl halidein the presence of base to yield the ester. Other methods for convertingGABA analogs to esters or thioesters are well within the purview of theskilled artisan in view of the references provided herein.

[0258] One method for synthesis of compounds of Formulae (I)-(IX), wheren is 0, involves the reaction of an appropriate lactol with a isocyanatederivative of a GABA analog, as illustrated specifically for the5-membered compound of Formula (II) in Scheme 1. Note that othercompounds (i.e., those of Formulae (III)-(X)) may be synthesized in asimilar fashion from an appropriate lactol.

[0259] Lactol (11) is reacted with isocyanate (13) in an appropriatesolvent (e.g., toluene) at a temperature between 0° C. and 120° C.,preferably between 25° C. and 120° C., in the presence of a base (e.g.,DBU, Et₃N, pyridine, DIEA, etc.) to afford a compound of Formula (II).Lactol (11) may be obtained from commercial sources or may be preparedby methods well known in the art. For example, addition oforganometallic reagents (e.g., alkyl lithium, Grignard reagents) orhydride reagents (e.g., LiAlH(O'Bu)₃, NaBH₄, LiAlH₄ or Na₂Fe(CO)₄) tocyclic anhydride (15) provides lactol (11) as illustrated in Scheme 2.

[0260] Five-membered lactols (11) and six-membered lactols (21) are alsoreadily accessible by tautomerization of the α, γ-carboxyaldehydes (17)and α,δ-carboxyaldehydes (19) respectively, as shown in Scheme 3.Compounds (17) and (19) in turn are available by methods well known tothe skilled artisan.

[0261] One method for preparation of isocyanate derivatives (13) beginswith an appropriate six-membered anhydride (23) as illustrated in Scheme4. The anhydride ring is opened by reaction with an alcohol or thiolnucleophile to afford carboxylic acid (25), which may be converted to anintermediate acyl azide in either a 2-step sequence (i.e., firstactivation of the carboxyl group as a mixed anhydride, acyl halide orsynthetic equivalent and then displacement with azide) or directly(i.e., by treatment with Ph₂P(O)N₃). Curtius rearrangement of the acylazide intermediate by thermolysis in an appropriate solvent (e.g.,toluene) at a temperature between 0° C. and 120° C. affords isocyanate(13). Optionally, the isocyanate is not isolated but rather is generatedin situ and quenched by reaction with lactol (11) to afford the desiredproduct of Formula (II).

[0262] Another method for synthesis of compounds of Formulae (I)-(X)involves activation of an appropriate lactol by treatment with phosgeneor its synthetic equivalent (27) (e.g., triphosgene,carbonyldiimidazole, p-nitrophenylchloroformate) to provide (29), whichmay be reacted with GABA analog derivative (31) to afford the desiredproduct, as illustrated specifically for the 5-membered compound ofFormula (II) in Scheme 5. Note that other compounds (of Formulae(III)-(X)) may be synthesized in a similar fashion from the appropriatelactol.

[0263] Alternatively compounds of Formulae (I)-(X) can be prepared fromactivated lactol (29) in a stepwise fashion as illustrated in Scheme 6.Here reaction of (29) with an α-amino acid, optionally protected as acarboxylate ester, affords intermediate (32), which upon deprotection,if necessary, provides compound (34). Compound (34) may be coupled toGABA analog (36) using standard peptide coupling reagents well known inthe art.

[0264] Another method for synthesis of compounds of Formulae (I)-(X)proceeds via carbonylation of GABA analog derivative (31) to anintermediate carbamic acid, which may be captured by an in situalkylation (Butcher, Synlett, 1994, 825-6; Ferres et al., U.S. Pat. No.4,036,829). Carbon dioxide gas may be added to a solution containing(31) and a base (e.g., Cs₂CO₃, Ag₂CO₃, AgO) in polar diprotic solvent(e.g., DMF, NMP). The activated halide may be added, optionally in thepresence of iodide ion as a catalyst, to the solution and the reactioncontinued until complete. This method is illustrated in Scheme 7 for thepreparation of compounds of Formula (II) and (V), from saturated andunsaturated halides (33) and (35), respectively. Compounds of Formula(III), (IV), (VI)-(X) may be similarly prepared from an appropriatecyclic halide.

[0265] Alternatively compounds of Formulae (I)-(X) may be prepared in astepwise fashion as illustrated in Scheme 8. Carbonylation andalkylation of carboxyl protected α-amino acid (30) providesintermediates (32) and (38), which upon deprotection are coupled to GABAanalog (36) as previously described in Scheme 6.

[0266] Another method for synthesis of compounds of Formulae (I)-(X)relies upon oxidation of ketocarbamate derivatives of GABA analogs, asdisclosed in a copending U.S. patent application Ser. No.______ entitled“Methods for Synthesis of Prodrugs from 1-Acyl-Alkyl Derivatives andCompositions.” As illustrated in Scheme 9, oxidation of ketocarbamates(37) and (39) affords compounds of Formulae (III) and (IV). Preferredsolvents for this reaction will dissolve, at least partially, both theoxidant and the ketocarbamate and will be inert to the reactionconditions. Preferred solvents include, but are not limited to,t-butanol, diethylether, acetic acid, hexane, dichloroethane,dichloromethane, ethyl acetate, acetonitrile, methanol, chloroform andwater. Generally, the oxidant may be an organism (e.g., yeast orbacteria), or a chemical reagent (e.g., an enzyme or peroxide), andpreferred oxidants include those, which have been successfully used inBaeyer-Villager oxidations of ketones to esters or lactones (Strukul,Angnew. Chem. Int. Ed., 1998, 37, 1198; Renz et al., Eur. J Org. Chem.1999, 737; Beller et al., in “Transitions Metals in Organic Synthesis”Chapter 2, Wiley VCH; Stewart, Current Organic Chemistry, 1998, 2, 195;Kayser et al., Synlett, 1999, 1, 153).

[0267] In one embodiment, the oxidant is yeast (e.g., Saccharomycescerevisiae) or bacteria (e.g., Acinetobacter sp. NCIB 9871). In anotherembodiment, the oxidant is a peroxide (preferably, H₂O₂, t-BuOOH or(TMS)₂O₂) or a peroxyacid (preferably, CF₃CO₃H, MeCO₃H, m-CPBA,monopermaleic acid, mono-o-perphthalic acid, 3,5 dinitroperbenzoic acid,o-nitroperbenzoic acid, m-nitroperbenzoic acid, p-nitroperbenzoic acid,performic acid, perbenzoic acid, persulfuric acid, or a salt thereof).In still another embodiment, the oxidant is an enzyme and oxygen.Preferably, the enzyme is cyclohexanone monooxygenase.

[0268] Other compounds of the invention may also be prepared from anappropriate ketocarbamate derivative via Baeyer-Villiger oxidation.Preferably, as is well known to the skilled artisan, such compounds donot contain functional groups susceptible to decomposition or furthertransformation under the reaction conditions.

[0269] Ketocarbamates (37) and (39) may be prepared from thecorresponding cyclic α-hydroxyketone compounds either directly, viareaction with isocyanate (13) (see Scheme 1 above), or by conversion ofthe α-hydroxyketone compound to a haloformate or activated carbonateintermediate and subsequent reaction with compound (31), as illustratedin Scheme 5. For cyclic α-hydroxyketones that are easily dimerized undernormal conditions (e.g., lower 2-hydroxycycloalkanones) the keto moietymay be protected until carbamate formation is completed. For example, asshown in Scheme 10, dialkyl ketal (41) serves as a masked2-hydroxycyclohexanone precursor, which may be converted toketocarbamate (39) by acidic hydrolysis.

[0270] Alternatively ketocarbamate (39) can be prepared in a stepwisemanner via the α-amino acid carbamate (43) as illustrated in Scheme 11,following the coupling methodologies used in Scheme 6 and 8.

4.4 Therapeutic Uses of the Compounds of the Invention

[0271] In accordance with the invention, a compound and/or compositionof the invention is administered to a patient, preferably a human,suffering from epilepsy, depression, anxiety, psychosis, faintnessattacks, hypokinesia, cranial disorders, neurodegenerative disorders,panic, pain (especially, neuropathic pain and muscular and skeletalpain), inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders or ethanol withdrawal syndrome. Further, incertain embodiments, the compounds and/or compositions of the inventionare administered to a patient, preferably a human, as a preventativemeasure against various diseases or disorders. Thus, the compoundsand/or compositions of the invention may be administered as apreventative measure to a patient having a predisposition for epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especially,neuropathic pain and muscular and skeletal pain), inflammatory disease(i.e., arthritis), insomnia, gastrointestinal disorders and ethanolwithdrawal syndrome. Accordingly, the compounds and/or compositions ofthe invention may be used for the prevention of one disease or disorderand concurrently treating another (e.g., prevention of psychosis whiletreating gastrointestinal disorders; prevention of neuropathic painwhile treating ethanol withdrawal syndrome).

[0272] The suitability of the compounds and/or compositions of theinvention in treating epilepsy, depression, anxiety, psychosis,faintness attacks, hypokinesia, cranial disorders, neurodegenerativedisorders, panic, pain (especially neuropathic pain and muscular andskeletal pain), inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders and ethanol withdrawal syndrome may bedetermined by methods described in the art (See, e.g., Satzinger et al.,U.S. Pat. No. 4,024,175; Satzinger et al., U.S. Pat. No.4,087,544;Woodruff, U.S. Pat. No.5,084,479; Silverman et al., U.S. Pat.No.5,563,175; Singh, U.S. Pat. No.6,001,876; Horwell et al., U.S. Pat.No. 6,020,370; Silverman et al., U.S. Pat. No.6,028,214; Horwell et al.,U.S. Pat. No. 6,103,932; Silverman et al., U.S. Pat. No. 6,117,906;Silverman, International Application No. WO 92/09560; Silverman et al.,International Application No. WO 93/23383; Horwell et al., InternationalApplication No. WO 97/29101, Horwell et al., International ApplicationNo. WO 97/33858; Horwell et al., International Application No. WO97/33859; Bryans et al., International Application No. WO 98/17627;Guglietta et al., International Application No. WO 99/08671; Bryans etal., International Application No. WO 99/21824; Bryans et al.,International Application No. WO 99/31057; Magnus-Miller et al.,International Application No. WO 99/37296; Bryans et al., InternationalApplication No. WO 99/31075; Bryans et al., International ApplicationNo. WO 99/61424; Pande, International Application No. WO 00/23067;Bryans, International Application No. WO 00/31020; Bryans et al.,International Application No. WO 00/50027; and Bryans et al,International Application No. WO 02/00209). Procedures for using thecompounds and/or compositions of the invention for treating epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especiallyneuropathic pain and muscular and skeletal pain), inflammatory disease(i.e., arthritis), insomnia, gastrointestinal disorders and ethanolwithdrawal syndrome have also been described in the art (see referencesabove). Thus, it is well with the capability of those of skill in theart to assay and use the compounds and/or of the invention to treatepilepsy, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain(especially, neuropathic pain and muscular and skeletal pain),inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders and ethanol withdrawal syndrome.

4.5 Therapeutic/Prophylactic Administration

[0273] The compounds and/or compositions of the invention may beadvantageously used in human medicine. As previously described inSection 4.4 above, compounds and compositions of the invention areuseful for the treatment or prevention of epilepsy, depression, anxiety,psychosis, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, panic, pain (especially, neuropathic painand muscular and skeletal pain), inflammatory disease (i.e., arthritis),insomnia, gastrointestinal disorders or ethanol withdrawal syndrome.

[0274] When used to treat or prevent the above disease or disorderscompounds and/or compositions of the invention may be administered orapplied singly, in combination with other agents. The compounds and/orcompositions of the invention may also be administered or appliedsingly, in combination with other pharmaceutically active agents,including other compounds of the invention.

[0275] The current invention provides methods of treatment andprophylaxis by administration to a patient of a therapeuticallyeffective amount of a composition or compound of the invention. Thepatient may be an animal, is more preferably a mammal, and mostpreferably a human.

[0276] The present compounds and/or compositions of the invention, whichcomprise one or more compounds of the invention, are preferablyadministered orally. The compounds and/or compositions of the inventionmay also be administered by any other convenient route, for example, byinfusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa,etc.). Administration can be systemic or local. Various delivery systemsare known, (e.g., encapsulation in liposomes, microparticles,microcapsules, capsules, etc.) that can be used to administer a compoundand/or composition of the invention. Methods of administration include,but are not limited to, intradermal, intramuscular, intraperitoneal,intravenous, subcutaneous, intranasal, epidural, oral, sublingual,intranasal, intracerebral, intravaginal, transdermal, rectally, byinhalation, or topically, particularly to the ears, nose, eyes, or skin.

[0277] In particularly preferred embodiments, the compounds of theinvention can be delivered via sustained release systems, preferablyoral sustained release systems. In one embodiment, a pump may be used(see Langer, supra; Sefton, 1987, CRC Crit Ref Blamed Eng. 14:201;Saudek et al., 1989, N. Engl. J. Med. 321:574).

[0278] In another embodiment, polymeric materials can be used (see“Medical Applications of Controlled Release,” Langer and Wise (eds.),CRC Pres., Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,”Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, N.Y.(1984); Ranger and Peppas, 1983, J Macromol. Sci. Rev. Macromol Chem.23:61; see also Levy et al., 1985, Science 228: 190; During et al.,1989, Ann. Neurol. 25:351; Howard et al, 1989, J. Neurosurg. 71:105). Ina preferred embodiment, polymeric materials are used for oral sustainedrelease delivery. Preferred polymers include sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred,hydroxypropylmethylcellulose). Other preferred cellulose ethers havebeen described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3)1-9). Factors affecting drug release are well known to the skilledartisan and have been described in the art (Bamba et al., Int. J.Pharm., 1979, 2, 307).

[0279] In another embodiment, enteric-coated preparations can be usedfor oral sustained release administration. Preferred coating materialsinclude polymers with a pH-dependent solubility (i.e., pH-controlledrelease), polymers with a slow or pH-dependent rate of swelling,dissolution or erosion (i.e., time-controlled release), polymers thatare degraded by enzymes (i.e., enzyme-controlled release) and polymersthat form firm layers that are destroyed by an increase in pressure(i.e., pressure-controlled release).

[0280] In still another embodiment, osmotic delivery systems are usedfor oral sustained release administration (Verma et al., Drug Dev. Ind.Pharm., 2000, 26:695-708). In a preferred embodiment, OROS™ osmoticdevices are used for oral sustained release delivery devices (Theeuweset al., U.S. Pat. No. 3,845,770; Theeuwes et al., U.S. Pat. No.3,916,899).

[0281] In yet another embodiment, a controlled-release system can beplaced in proximity of the target of the compounds and/or composition ofthe invention, thus requiring only a fraction of the systemic dose (see,e.g., Goodson, in “Medical Applications of Controlled Release,” supra,vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussedin Langer, 1990, Science 249:1527-1533 may also be used.

[0282] The compounds and/or compositions of the invention preferablyprovide GABA analogs (e.g., gabapentin and pregablin) upon in vivoadministration to a patient. While not wishing to bound by theory, thepromoiety or promoieties of the compounds and/or compositions of theinvention may be cleaved either chemically and/or enzymatically. One ormore enzymes present in the stomach, intestinal lumen, intestinaltissue, blood, liver, brain or any other suitable tissue of a mammal mayenzymatically cleave the promoiety or promoieties of the compoundsand/or compositions of the invention. The mechanism of cleavage is notimportant to the current invention. Preferably, GABA analogs formed bycleavage of prodrugs from the compounds of the invention do not containsubstantial quantities of lactam contaminant (preferably, less than 0.5%by weight, more preferably, less than 0.2% by weight, most preferablyless than 0.1% by weight). The extent of release of lactam contaminantfrom the prodrugs of this invention may be assessed using the standardin vitro analytical methods.

[0283] While not wishing to bound by theory, the promoiety orpromoieties of the compounds and/or compositions of the invention may becleaved prior to absorption by the gastrointestinal tract (e.g., withinthe stomach or intestinal lumen) and/or after absorption by thegastrointestinal tract (e.g., in intestinal tissue, blood, liver orother suitable tissue of a mammal). If the promoiety or promoieties ofthe compounds of the invention are cleaved prior to absorption by thegastrointestinal tract, the resulting GABA analogs may be absorbed intothe systemic circulation conventionally (e.g., via the large neutralamino acid transporter located in the small intestine). If the promoietyor promoieties of the compounds of the invention are cleaved afterabsorption by the gastrointestinal tract, these GABA analog prodrugs mayhave the opportunity to be absorbed into the systemic circulation eitherby passive diffusion, active transport or by both passive and activeprocesses.

[0284] If the promoiety or promoieties of the compounds of the inventionare cleaved after absorption by the gastrointestinal tract, these GABAanalog prodrugs may have the opportunity to be absorbed into thesystemic circulation from the large intestine. In this situation, thecompounds and/or compositions of the invention are preferablyadministered as sustained release systems. In a preferred embodiment,the compounds of the invention are delivered by oral sustained releaseadministration. Preferably, in this embodiment, the compounds of theinvention are administered twice per day (more preferably, once perday).

4.6 Compositions of the Invention

[0285] The present compositions contain a therapeutically effectiveamount of one or more compounds of the invention, preferably in purifiedform, together with a suitable amount of a pharmaceutically acceptablevehicle, which so as to provide the form for proper administration to apatient. When administered to a patient, the compounds of the inventionand pharmaceutically acceptable vehicles are preferably sterile. Wateris a preferred vehicle when the compound of the invention isadministered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid vehicles, particularlyfor injectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The present compositions, if desired, canalso contain minor amounts of wetting or emulsifying agents, or pHbuffering agents. In addition, auxiliary, stabilizing, thickening,lubricating and coloring agents may be used.

[0286] In one embodiment, the compositions of the invention are free oflactam side products formed by intramolecular cyclization. In apreferred embodiment, the compositions of the invention are stable toextended storage (preferably, greater than one year) without substantiallactam formation (preferably, less than 0.5% lactam by weight, morepreferably, less than 0.2% lactam by weight, most preferably, less than0.1% lactam by weight).

[0287] Pharmaceutical compositions comprising a compound of theinvention may be manufactured by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxiliaries, which facilitate processing of compounds of the inventioninto preparations which can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen.

[0288] The present compositions can take the form of solutions,suspensions, emulsion, tablets, pills, pellets, capsules, capsulescontaining liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. In one embodiment, the pharmaceuticallyacceptable vehicle is a capsule (see e.g., Grosswald et al., U.S. Pat.No. 5,698,155). Other examples of suitable pharmaceutical vehicles havebeen described in the art (see Remington's Pharmaceutical Sciences,Philadelphia College of Pharmacy and Science, 17th Edition, 1985).Preferred compositions of the invention are formulated for oraldelivery, particularly for oral sustained release administration.

[0289] Compositions for oral delivery may be in the form of tablets,lozenges, aqueous or oily suspensions, granules, powders, emulsions,capsules, syrups, or elixirs, for example. Orally administeredcompositions may contain one or more optionally agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry coloring agentsand preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, where in tablet or pill form, the compositionsmay be coated to delay disintegration and absorption in thegastrointestinal tract, thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compounds of the invention. In these later platforms, fluidfrom the environment surrounding the capsule is imbibed by the drivingcompound, which swells to displace the agent or agent compositionthrough an aperture. These delivery platforms can provide an essentiallyzero order delivery profile as opposed to the spiked profiles ofimmediate release formulations. A time delay material such as glycerolmonostearate or glycerol stearate may also be used. Oral compositionscan include standard vehicles such as mannitol, lactose, starch,magnesium stearate, sodium saccharine, cellulose, magnesium carbonate,etc. Such vehicles are preferably of pharmaceutical grade.

[0290] For oral liquid preparations such as, for example, suspensions,elixirs and solutions, suitable carriers, excipients or diluents includewater, saline, alkyleneglycols (e.g., propylene glycol), polyalkyleneglycols (e.g., polyethylene glycol) oils, alcohols, slightly acidicbuffers between pH 4 and pH 6 (e.g., acetate, citrate, ascorbate atbetween about 5 mM to about 50 mM) etc. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcarnitines and the likemay be added.

[0291] Compositions for administration via other routes may also becontemplated. For buccal administration, the compositions may take theform of tablets, lozenges, etc. formulated in conventional manner.Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a compoundof the invention with a pharmaceutically acceptable vehicle. Preferably,the pharmaceutically acceptable vehicle is a liquid such as alcohol,water, polyethylene glycol or a perfluorocarbon. Optionally, anothermaterial may be added to alter the aerosol properties of the solution orsuspension of compounds of the invention. Preferably, this material isliquid such as an alcohol, glycol, polyglycol or a fatty acid. Othermethods of formulating liquid drug solutions or suspension suitable foruse in aerosol devices are known to those of skill in the art (see,e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No.5,556,611). A compound of the invention may also be formulated in rectalor vaginal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides. In addition to the formulations described previously, acompound of the invention may also be formulated as a depot preparation.Such long acting formulations may be administered by implantation (forexample, subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, a compound of the invention may beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

[0292] When a compound of the invention is acidic, it may be included inany of the above-described formulations as the free acid, apharmaceutically acceptable salt, a solvate or hydrate. Pharmaceuticallyacceptable salts substantially retain the activity of the free acid, maybe prepared by reaction with bases and tend to be more soluble inaqueous and other protic solvents than the corresponding free acid form.

4.7 Methods of Use And Doses

[0293] A compound of the invention, or compositions thereof, willgenerally be used in an amount effective to achieve the intendedpurpose. For use to treat or prevent diseases or disorders such asepilepsy, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain(especially, neuropathic pain and muscular and skeletal pain),inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders or ethanol withdrawal syndrome the compounds of the inventionor compositions thereof, are administered or applied in atherapeutically effective amount.

[0294] The amount of a compound of the invention that will be effectivein the treatment of a particular disorder or condition disclosed hereinwill depend on the nature of the disorder or condition, and can bedetermined by standard clinical techniques known in the art aspreviously described. In addition, in vitro or in vivo assays mayoptionally be employed to help identify optimal dosage ranges. Theamount of a compound of the invention administered will, of course, bedependent on, among other factors, the patient being treated, the weightof the patient, the severity of the affliction, the manner ofadministration and the judgment of the prescribing physician.

[0295] For example, the dosage may be delivered in a pharmaceuticalcomposition by a single administration, by multiple applications orcontrolled release. In a preferred embodiment, the compounds of theinvention are delivered by oral sustained release administration.Preferably, in this embodiment, the compounds of the invention areadministered twice per day (more preferably, once per day). Dosing maybe repeated intermittently, may be provided alone or in combination withother drugs and may continue as long as required for effective treatmentof the disease state or disorder.

[0296] Suitable dosage ranges for oral administration are dependent onthe potency of the parent GABA analog drug, but are generally about0.001 mg to about 200 mg of a compound of the invention per kilogrambody weight. When the GABA analog is gabapentin, typical daily doses ofthe parent drug in adult patients are 900 mg/day to 3600 mg/day and thedose of gabapentin prodrug may be adjusted to provide an equivalentmolar quantity of gabapentin. Other GABA analogs may be more potent thangabapentin (e.g., pregabalin), and lower doses may be appropriate forboth the parent drug and any prodrug (measured on an equivalent molarbasis). Dosage ranges may be readily determined by methods known to theskilled artisan.

[0297] The compounds of the invention are preferably assayed in vitroand in vivo, for the desired therapeutic or prophylactic activity, priorto use in humans. For example, in vitro assays can be used to determinewhether administration of a specific compound of the invention or acombination of compounds of the invention is preferred for reducingconvulsion. The compounds of the invention may also be demonstrated tobe effective and safe using animal model systems.

[0298] Preferably, a therapeutically effective dose of a compound of theinvention described herein will provide therapeutic benefit withoutcausing substantial toxicity. Toxicity of compounds of the invention maybe determined using standard pharmaceutical procedures and may bereadily ascertained by the skilled artisan. The dose ratio between toxicand therapeutic effect is the therapeutic index. A compound of theinvention will preferably exhibit particularly high therapeutic indicesin treating disease and disorders. The dosage of a compound of theinventions described herein will preferably be within a range ofcirculating concentrations that include an effective dose with little orno toxicity.

4.8. Combination Therapy

[0299] In certain embodiments of the present invention, the compounds ofthe invention can be used in combination therapy with at least one othertherapeutic agent. The compound of the invention and the therapeuticagent can act additively or, more preferably, synergistically. In apreferred embodiment, a composition comprising a compound of theinvention is administered concurrently with the administration ofanother therapeutic agent, which can be part of the same composition asthe compound of the invention or a different composition. In anotherembodiment, a composition comprising a compound of the invention isadministered prior or subsequent to administration of anothertherapeutic agent.

5. EXAMPLES

[0300] The invention is further defined by reference to the followingexamples, which describe in detail preparation of compounds andcompositions of the invention and assays for using compounds andcompositions of the invention. It will be apparent to those skilled inthe art that many modifications, both to materials and methods, may bepracticed without departing from the scope of the invention.

[0301] In the examples below, the following abbreviations have thefollowing meanings. If an abbreviation is not defined, it has itsgenerally accepted meaning. Atm = atmosphere Boc = tert-butyloxycarbonylCbz = carbobenzyloxy CPM = counts per minute DCC =dicyclohexylcarbodiimide DMAP = 4-N,N-dimethylaminopyridine DMEM =Dulbecco's minimun eagle medium DMF = N,N-dimethylformamide DMSO =dimethylsulfoxide Fmoc = 9-fluorenylmethyloxycarbonyl g = gram h = hourHBSS = Hank's buffered saline solution L = liter LC/MS = liquidchromatography/mass spectroscopy M = molar min = minute mL = millilitermmol = millimoles MRM = multiple reaction monitoring NADPH = reducednicotinamide adenine dinucleotide phosphate NHS = N-hydroxysuccinimidePBS = phosphate buffered saline THF = tetrahydrofuran TFA =trifluoroacetic acid TMS = trimethylsilyl μL = microliter μM =micromolar v/v = volume to volume

5.1 Example 1 Preparation of1-{{[(ε-Caprolacton-6-yl)oxy]carbonyl}aminomethyl}-1-Cyclohexane AceticAcid (44)

[0302]

Step A: 2,2-Dimethoxycyclohex-1-yl Chloroformate (45)

[0303] To a stirred solution of 2,2′-dimethoxycyclohexanol (1.49 mL, 10mmol) in dichloromethane (25 mL) under nitrogen atmosphere at 0° C. wasadded pyridine (1.21 mL, 15 mmol) followed by a solution of triphosgene(1.48 g, 5 mmol) in dichloromethane (25 mL). The reaction mixture wasstirred at 0° C. for 30 minutes to provide compound 45 which was used inthe next step without further purification.

Step B:1-{{[(Cyclohexanon-2-yl)oxy]carbonyl}aminomethyl}-1-CyclohexaneAcetic Acid (46)

[0304] To a stirred solution of gabapentin (2.56 g, 15 mmol) andchlorotrimethylsilane (3.7 mL, 30 mmol) in dichloromethane (25 mL) at 0°C. under nitrogen atmosphere was added triethylamine in portions. Afterhaving stirred for 15 min at 0° C. the chloroformate (45) was addeddropwise into the reaction mixture. The mixture was stirred at 0° C. for2 h and then at room temperature for 2 h (monitored by TLC). Thereaction mixture was concentrated in vacuo and the residue was pouredinto cold water (50 mL) and then acidified to about pH 5.0 using 0.1 NHCl. The crude product was then extracted using ethyl acetate (2×50 mL).The combined extracts were washed with brine (40 mL), dried over MgSO₄and the solvent removed in vacuo. The crude product was dissolved inacetone (25 mL) and treated using Amberlyst-15 (1.0 g) for 1.5 h(monitored by LC/MS). The reaction mixture was filtered and thefiltercake was washed with acetone (2×15 mL). The combined extracts wereevaporated under reduced pressure and the residue was purified usingprep-HPLC/MS method to provide 1.71 g (55% yield) of compound 46 as awhite solid. ¹H NMR (CDCl₃, 400 MHz): 5.42 (1H, t), 5.12 (1H, m),3.35−3.16 (2H, m), 2.39 (4H, m), 1.80−1.40 (16H, m). MS (ESI):m/z=310.27 (M−H⁻), and 312.28 (M+H⁺).

Step C: 1-{{[(ε-Caprolacton-6-yl)oxy]carbonyl}aminomethyl}-1-CyclohexaneAcetic Acid (44)

[0305] To a stirred solution of (46) (0.31 g, 1 mmol) in dichloromethane(10 mL) was added mCPBA (0.68 g, 4 mmol) and Na₂HPO₄ (0.56 g, 4 mmol).The mixture was stirred at room temperature for 12 h (monitored byLC/MS), then concentrated in vacuo. The resulting residue was dissolvedin water and then acidified to about pH 5.0 using 0.1N HCl. The aqueoussolution was extracted using ethyl acetate (3×25 mL). The combinedextracts were washed with brine (50 mL), dried over Na₂SO₄ andconcentrated in vacuo. The resulting residue was purified usingprep-HPLC/MS to provide 0.27 g (85%) of compound 44 as light yellowviscous liquid. ¹H NMR (CDCl₃, 400 MHz): δ6.40 (1H, m); 5.65 (1H, t);3.31−3.25 (2H, m); 2.40−2.22 (4H, m); 1.60−1.30 (16H, m). MS (ESI):m/z=326.18 (M−H⁻), 328.26 M+H⁺). 328.26 (M+H⁺).

5.2 Example 2 Preparation of1-{{[(δ-Valerolacton-2(R)-yl)oxy]carbonyl}aminomethyl}-1-CyclohexaneAcetic Acid (47)

[0306]

Step A:1-{{{[2(R)-Acetoxycyclopent-1(R)-yl]oxy}carbonyl}aminomethyl}-1-CyclohexaneAcetic Acid (48)

[0307] To a stirred solution of (1R,2R)-trans-2-acetoxy-1-cyclopentanol(1.0 g, 6.9 mmol) in dichloromethane (25 mL) at 0° C. under nitrogenatmosphere was added pyridine (0.88 mL, 10.4 mmol) followed by asolution of triphosgene (1.03 g, 3.5 mmol) in dichloromethane (25 mL).The reaction mixture was stirred at 0° C. for 30 min. to provide thecorresponding 2(R)-acetoxycyclopent-1(R)-yl chloroformate which wascarried to next step without further purification.

[0308] In a separate reaction flask, to a stirred solution of gabapentin(1.8 g, 10 mmol) and triethylamine (4.3 mL, 31 mmol) in dichloromethane(100 mL) at 0° C. under nitrogen atmosphere, was added dropwise asolution of chlorotrimethylsilane (2.6 mL, 21 mmol) in dichloromethane(10 mL). After stirring for 30 min at 0° C.,2(R)-acetoxycyclopent-1(R)-yl chloroformate was added dropwise into thereaction mixture. The resulting mixture was stirred at 0° C. for 2 h andthen at room temperature for 2 h (monitored by TLC). The reactionmixture was then concentrated in vacuo and the resulting residue waspoured into cold water (50 mL), acidified to about pH 5.0 using 0.1 NHCl, then extracted using ethyl acetate (2×50 mL). The combined extractswere washed with brine (40 mL), dried over MgSO₄ and concentrated invacuo. The crude product was purified using flash chromatography onsilica gel using hexane/ethyl acetate (2:1) as eluant to afford 2.0 g(84%) of compound 48 as a colorless oil. ¹H NMR (400 MHz, CDCl₃):δ1.31-1.78 (14H, m); 2.03-2.04 (5H, m); 2.31 (2H, s); 3.20 (2H, t, J=6.4Hz); 5.07−4.97 (2H, m), 5.20 (1H, broad s). MS (ESI): m/z=340.25 (M−H⁻).

Step B:1-{{{[2(R)-Hydroxycyclopent-1(R)-yl]oxy}carbonyl}aminomethyl}-1-CyclohexaneAcetic Acid (49)

[0309] To a stirred solution of compound (48) (2.0 g, 5.9 mmol) inmethanol (25 mL) was added a solution of NaOH (0.8 g, 20 mmol) in 20 mLof water. The reaction mixture was stirred at room temperature for 2 h(monitored by TLC). The reaction mixture was acidified to about pH 5.0using 0.1 N HCl and then extracted using ethyl acetate (2×50 mL). Thecombined extracts were washed with brine (40 mL), dried over MgSO₄ andconcentrated in vacuo. The crude product was purified using flashchromatography on silica gel using hexane/ethyl acetate (1:1) as eluantto provide 1.3 g (75%) of compound (49) as a colorless oil. ¹H NMR (400MHz, CDCl₃): δ1.36-1.78 (14H, m); 1.99-2.12 (2H, m); 2.34 (2H, s); 3.23(2H, d, J=6.4 Hz); 4.09 (1H, m); 5.26 (1H, t, J=6.4 Hz); 5.89 (1H, m).MS (ESI): m/z=298.23 (M−H⁻).

Step C: Benzyl1-{{{[2(R)-Hydroxycyclopent-1(R)-yl]oxy}carbonyl}aminomethyl}-1-CyclohexaneAcetate (50)

[0310] To a stirred solution of compound (49) (0.5 g, 1.67 mmol),1,3-dicyclohexylcarbodiimide (1.0 g, 5.0 mmol) and DMAP (19 mg, 0.16mmol) in dichloromethane (100 mL) at room temperature under nitrogenatmosphere was added benzyl alcohol (1.1 mL, 10 mmol). The reactionmixture was stirred at room temperature for 15 h (monitored by tlc andLC/MS), then filtered, and the white solid was washed withdichloromethane (2×15 mL). The combined filtrates were washed with water(2×25 mL), dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was purified using flash chromatography on silica gel usinghexane/ethyl acetate (2:1) as eluant to provide 0.51 g (78%) of compound(50) as a colorless liquid. ¹H NMR (400 MHz, CDCl₃): δ1.36-1.75 (14H,m); 1.99-2.10 (2H, m); 2.35 (2H, s); 3.17 (2H, d, J=6.8 Hz); 4.05 (1H,m); 4.65 (1H, m); 5.12 (2H, s); 5.34 (1H, t,J=6.8 Hz); 7.36 (5H, m). MS(ESI): m/z=390.22 (M+H⁺).

Step D: Benzyl1-{{{[2-Oxo-cyclopent-1(R)-yl]oxy}carbonyl}aminomethyl}-1-CyclohexaneAcetate (51)

[0311] To a stirred solution of compound (50) (0.50 g, 1.3 mmol) indichloromethane (15 mL) was added pyridinium chlorochromate (0.55 g, 2.6mmol) followed by NaOAc (0.21 g, 2.57 mmol) at room temperature. Theresulting reaction was stirred overnight at room temperature (monitoredby LC/MS), then filtered. The solid was washed with dichloromethane(2×25 mL) and the combined filtrates were washed with water (2×25 mL),dried over MgSO₄ and concentrated in vacuo to provide compound 51 whichwas used in the next step without further purification. MS (ESI):m/z=388.38 (M+H⁺).

Step E: Benzyl1-{{[(δ-valerolacton-2(R)-yl)oxy]carbonyl}aminomethyl}-1-CyclohexaneAcetate (52)

[0312] To a stirred solution of compound (51) (0.50 g, 1.2 mmol) indichloromethane (20 mL) was added 3-chloroperoxybenzoic acid (0.82 g,4.8 mmol) and Na₂HPO₄ (0.68 g, 4.8 mmol). The resulting reaction wasstirred at room temperature for 12 h (monitored by LC/MS), thenconcentrated in vacuo and the resulting residue was dissolved in waterand acidified to about pH 5.0 using 0.1N HCl. The reaction mixture wasextracted using ethyl acetate (3×25 mL), and the combined extracts werewashed with brine (50 mL), dried over Na₂SO₄ and concentrated in vacuo.The resulting residue was purified using preparative-HPLC/MS to afford0.20 g (41%) of compound (52) as a colorless oil. ¹H NMR (400 MHz,CDCl₃): δ1.32-1.60 (10H, m); 1.82-1.92 (2H, m); 2.00-2.11 (2H, m); 2.36(2H, s); 2.52-2.67 (2H, m); 3.20 (2H, m); 5.20 (2H, s); 5.49 (1H, broadt), 6.50 (1H, t, J=4.0 Hz); 7.32-7.40 (5H, m). MS (ESI): m/z=404.22(M+H⁺).

Step F:1-{{[(δ-Valerolacton-2(R)-yl)oxy]carbonyl}aminomethyl}-1-CyclohexaneAcetic Acid (47)

[0313] To a stirred solution of benzyl ester (52) (0.17 g, 0.42 mmol) inethyl acetate (5 mL) was added 50 mg of 5% w/w palladium on carbon(Pd/C). The resulting reaction was stirred overnight at room temperatureunder a hydrogen atmosphere (monitored by LC/MS). The reaction mixturewas then filtered through a Celite® pad and the pad was washed withethyl acetate (2×10 mL). The combined filtrates were concentrated invacuo to afford 0.12 g (99%) of compound (47) as a white solid.

[0314]¹HNMR (400 MHz, CDCl₃): δ1.40-1.54 (10H, m); 1.84-1.92 (2H, m);2.00-2.13 (2H, m); 2.35 (2H, s); 2.52-2.67 (2H, m); 3.26 (2H, d, J=6.4Hz); 5.39 (1H, t, J=6.4 Hz); 6.51 (¹H, t, J=4 Hz). MS (ESI): m/z=312.26(M−H⁻).

5.3 Example 3 Preparation-of1-{{[(3-Oxo-1,3-dihydro-isobenzofuran-1-yl)-oxy]carbonyl}aminomethyl}-1-CyclohexaneAcetic Acid (53)

[0315]

Step A: (1-Allyloxycarbonylmethyl-1-Cyclohexane Acetic Acid (54)

[0316] To a stirred suspension of sodium hydride (0.84 g, 35 mmol) indry tetrahydrofuran (200 mL) under nitrogen atmosphere at 0° C. wasadded allyl alcohol (2.0 mL, 30 mmol) dropwise. The resulting reactionwas stirred at 0° C. for 30 min and then at room temperature for 2hours. A solution of 3-oxa-spiro[5,5]undecane-2,3-dione (4.5 g, 25 mmol)in dry tetrahydrofuran (10 mL) was then added dropwise to the reactionmixture at 0° C. The resulting reaction was stirred at 0° C. for 30 min,at room temperature for 3 h (monitored by TLC and LC/MS), and thenconcentrated in vacuo. The resulting residue was poured into a saturatedaqueous NH₄Cl solution (100 mL) and the resulting mixture was extractedusing ethyl acetate (2×100 mL). The combined extracts were washed withbrine (100 mL), dried over MgSO₄ and concentrated in vacuo. Theresulting residue was purified using flash chromatography on silica gelusing hexane/ethyl acetate (4:1) as eluant to afford 3.2 g of compound(54) as a colorless liquid in (50% yield). ¹H NMR (400 MHz, CDCl₃):δ1.50 (10H, m); 2.58 (4H, broad s); 4.57-4.59 (2H, m); 5.21-5.25 (1H,m); 5.29-5.35 (1H, m); 5.86-5.96 (1H, m). MS (ESI): m/z=239.29 (M−H⁻).

Step B:1-{{[(3-Oxo-1,3-dihydro-isobenzofuran-1-yl)-oxy]carbonyl}aminomethyl}-1-CyclohexaneAcetic Acid Allyl Ester (55)

[0317] To a stirred solution of (54) (3.2 g, 12 mmol) and ethylchloroformate (1.4 mL, 15 mmol) in dry tetrahydrofuran (50 mL) at 0° C.under nitrogen atmosphere was added triethylamine (2.1 mL, 15 mmol)dropwise and the resulting reaction was allowed to stir for 15 min. Asolution of sodium azide (1.95 g, 30 mmol) in water (10 mL) was addedand the resulting reaction was stirred for 1 h (monitored by tlc), thenpoured into cold water (25 mL) and extracted using toluene (2×100 mL).The combined extracts were washed with brine (100 mL), dried over MgSO₄and filtered. The resulting solution was then heated at refluxed (˜110°C.) for 4 h to provide an isocyanate intermediate that was used in thenext step without further purification.

[0318] To a stirred solution of the isocyanate intermediate in toluenefrom above at room temperature was added 2-carboxybenzaldehyde (1.8 g,12 mmol) and the resulting reaction was allowed to stir at reflux for 15h (monitored by tlc). The reaction mixture was cooled to roomtemperature, concentrated in vacuo, and the resulting residue waspurified using flash chromatography on silica gel using hexane/ethylacetate (2:1) as eluant to provide 1.2 g of compound (55) as a whitesolid (25% yield). ¹H NMR (400 MHz, CDCl₃): δ1.39-1.55 (10H, m); 2.34(2H, s); 3.20-3.38 (2H, m); 4.56 (2H, d, J=6.0 Hz); 5.33−5.22 (2H, m);5.64 (1H, t, J=6.8 Hz); 5.84-5.94 (1H, m); 7.43 (1H, s); 7.60-7.66 (2H,dd, J=7.6 Hz); 7.74 (1H, t, J=7.6 Hz); 7.93 (1H, d, J=7.6 Hz). MS (ESI):m/z=388.36 (M+H⁺).

Step C:1-{{[(3-Oxo-1,3-dihydro-isobenzofuran-1-yl)-oxy]carbonyl}aminomethyl}-1-CyclohexaneAcetic Acid (53)

[0319] To a stirred solution of (55) (0.12 g, 0.31 mmol) in drytetrahydrofuran was added tetrakis(triphenylphosphine)-palladium(0) (5.5mg, 4.8×10⁻³ mmol) and formic acid (57 mg, 1.24 mmol). The resultingreaction was stirred at room temperature for 12 h (monitored by LC/MS),then filtered through a Celite® and activated charcoal pad. The pad waswashed with ethyl acetate (2×15 mL) and the combined filtrates werewashed with brine (20 mL), dried over MgSO₄ and concentrated in vacuo.The resulting residue was purified using preparative-LC/MS to provide 80mg of compound (53) as a white solid (74% yield). ¹H NMR (400 MHz,CDCl₃) δ1.35-1.58 (10H, m); 2.34 (2H, s); 3.23-3.40 (2H, m); 5.56 (1H,t, J=7.2 Hz); 7.42 (1H, s); 7.60-7.66 (2H, dd, J=7.6 Hz); 7.74 (1H, t,J=7.6 Hz); 7.91 (1H, d, J=7.6 Hz). MS (ESI): m/z=346.40 (M+H⁺).

5.4 Example 4 Standard Methods for Determination of Enzymatic Cleavageof Prodrugs in Vitro

[0320] The stability of novel prodrugs is evaluated in one or more invitro systems using tissues representative of those encountered in vivo(i.e., intestinal luminal contents, small intestinal cells, blood,liver, etc.) following methods known in the art. Tissues may be obtainedfrom any vertebrate species but most commonly are obtained from mouse,rat, hamster, guinea pig, rabbit, pig, dog, monkey or human sources.Fractions, homogenates, supernatants, extracts or other preparations ofthese tissues are obtained from suitable commercial sources (e.g.,Pel-Freez Biologicals, Rogers, AR, or GenTest Corporation, Woburn,Mass.), or prepared by methods well known in the art.

[0321] Representative conditions typically used for in vitro studiesconducted with these preparations are described in Table 1 below herein.For example, a prodrug (50 μM) is incubated with 90% human liver S9fraction containing 1.3 mM NADPH or a suitable NADPH-generating system(e.g., 1.3 mM NADP⁺, 3.3 mM glucose-6-phosphate, 0.4 U/mLglucose-6-phosphate dehydrogenase, 3.3 mM magnesium chloride and 0.95mg/mL potassium phosphate, pH 7.4). The mixture is incubated at 37° C.for one hour. Aliquots (50 μL) are removed at 0, 30, and 60 min andquenched with 0.1% trifluoroacetic acid in acetonitrile. Samples arethen centrifuged and analyzed by LC/MS. Similar conditions may be usedwith other homogenates, preparations or extracts of the tissuesencountered in vivo. For drugs that are poorly absorbed, a preferredprodrug is one that demonstrates at least 1% cleavage to produce thefree drug or an active metabolite thereof within a 60 minute period,when examined by one or more of methods III through XI as listed inTable 1. Additional biological matrices are examined when consideredrelevant to the distribution of the drug. Stability of prodrugs towardsspecific enzymes or enzyme mixtures (e.g., carboxylesterases,pancreatin, etc.) is also assessed in vitro by incubation with thepurified enzyme.

[0322] Concentrations of prodrug or of released drug in tissue extractswere determined by direct injection of quenched samples onto an AppliedBiosystems (Foster, Calif.) API 2000 LC/MS equipped with an Agilent(Palo Alto, Calif.) 1100 binary pump and autosampler. Separation wasachieved using a 3.5 μm Zorbax Ellipse XDB-C8 4.4×150 mm chromatographycolumn (Capital HPLC, Ltd., West Lothian, UK) heated to 45° C. duringthe analysis. The mobile phases were: 0.1% formic acid in water (A) and0.1% formic acid in acetonitrile (B). The gradient condition was: 2% Bfor 0.5 min, increasing to 90% B in 2.0 min, maintained for 2.5 min andreturning to 2% B for 2 min. A TurbolonSpray source was used on the API2000. For example, the analysis was performed in the positive ion modeand MRM (multiple reaction monitoring) transitions of 172.0/137.2 wereused in the analysis of gabapentin; appropriate MRM transitions wereused for prodrugs depending on structure. Ten microliters of the sampleextracts were injected. Peaks were integrated using Analyst quantitationsoftware. The method was linear for gabapentin and prodrugs over theconcentration range 0.002 to 10 μg/mL. TABLE 1 Standard Conditions forIn Vitro Evaluation of Prodrug Stability Tissue Prep Prodrug AdditionalIncubation Method Tissue Preparation Concn. Concn. Cofactors Condition IIntestinal Intestinal Wash or 90% 5 μM None 37° C. Luminal PancreaticJuice for 1 hr Contents II Intestinal Purified Enzymes (eg: 90% 5 μMNone 37° C. Luminal carboxypeptidase A, for 1 hr Contents pancreatin,etc.) III Small Cultured Enterocytes N/A 5 μM None 37° C. Intestinal for1 hr Cells IV Small S9 Fraction or 90% 5 μM NADPH or 37° C. IntestinalCytosol NADPH for 1 hr Cells generating system* V Small Microsomes 0.8mg 5 μM NADPH or 37° C. Intestinal protein/mL NADPH for 1 hr Cellsgenerating system* VI Blood Whole Blood, Plasma, 90% 5 μM None 37° C.Serum, etc. for 1 hr VII Liver Cultured Hepatocytes N/A 5 μM None 37° C.for 1 hr VIII Liver Precision Cut Liver N/A 5 μM None 37° C. Slices for1 hr IX Liver S9 Fraction or 90% 5 μM NADPH or 37° C. Cytosol NADPH for1 hr generating system* X Liver Microsomes 0.8 mg 5 μM NADPH or 37° C.protein/mL NADPH for 1 hr generating system* XI Liver Purified Enzymes1.0 U/mL 5 μM Enzyme 37° C. (e.g., porcine liver dependent for 1 hresterase) XII Biliary Bile 90% 5 μM None 37° C. Tract for 1 hr

5.5 Example 5 General Procedure for the Measurement of the Uptake ofGabapentin Following Administration of Gabapentin or a Cyclic Prodrug ofthe Invention Intracolonically in Rats

[0323] Sustained-release oral dosage forms, which release drug slowlyover periods of 6-24 hours, generally release a significant proportionof the dose within the colon. Thus, drugs suitable for use in suchsustained-release oral dosage forms will preferably exhibit good colonicabsorption. The suitability of gabapentin prodrugs for use in an oralsustained release dosage form can be assessed using the method describedbelow:

[0324] Rats are obtained commercially and are pre-cannulated in the boththe ascending colon and the jugular vein. The rats are then fastedovernight and until 4 hours post-dosing. Gabapentin or prodrugs areadministered as aqueous solutions directly into the colon via thecannula at a suitable dose, including, but not limited to 25 mg/kg.Blood samples (0.5 mL) are obtained from the jugular cannula atintervals over an 8 hour period following dosing and are quenchedimmediately by adding 0.3 mL of a solution of acetonitrile/methanol(1:1). The quenched samples are then processed for plasma bycentrifugation and the concentration of gabapentin or prodrug in theplasma is determined by LC/MS as described above. It is to be noted thatthe rats remain conscious during the course of this procedure.

[0325] Examples 6 and 7 below summarize the results obtained forCompounds (44) and (47), respectively, using the methodology describedin Example 5.

5.6 Example 6 Evaluation of Compound (44)

[0326]

[0327] Using the method of Example 5, following intracolonic dosing ofcompound (44) in rats, the maximum concentration of gabapentin in plasmawas 78% higher than the corresponding maximum concentration observedafter intracolonic dosing of gabapentin itself at an equimolar dose.

5.7 Example 7 Evaluation of Compound (47)

[0328]

[0329] Using the method of Example 5, following intracolonic dosing ofcompound (47) in rats, the maximum concentration of gabapentin in plasmawas 40% higher than the corresponding maximum concentration observedafter intracolonic dosing of gabapentin itself at an equimolar dose.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: n is 0 or 1; Y is O or S; X is alkyldiyl, substitutedalkyldiyl, arylalkyldiyl, substituted arylalkyldiyl, aryldiyl,substituted aryldiyl, cycloheteroalkyldiyl, substitutedcycloheteroalkyldiyl, heteroaryldiyl, substituted heteroaryldiyl,heteroarylalkyldiyl, substituted heteroarylalkyldiyl, heteroalkyldiyl orsubstituted heteroalkyldiyl; R⁴⁷ is hydrogen, alkyl, substituted alkyl,arylalkyl or substituted arylalkyl; R² is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, alkylamino, substituted alkylamino,alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substitutedalkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl,substituted alkylthio, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, aryloxy, substituted aryloxy, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy, or optionally, R⁴⁷ and R² taken together are alkyldiyl orsubstituted alkyldiyl; R³ and R⁶ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl; R⁴ and R⁵ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or optionally,R⁴ and R⁵ taken together are alkyldiyl, substituted alkyldiyl,heteroalkyldiyl, substituted heteroalkyldiyl, or together with thecarbon atom to which they are attached form a bridged cycloalkyl ring;R⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; and R⁴⁸ is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl,substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl.
 2. The compound of claim 1 having theformula:

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: n is 0 or 1; Y is O or S; X is alkyldiyl, substitutedalkyldiyl, arylalkyldiyl, substituted arylalkyldiyl, aryldiyl,substituted aryldiyl, cycloheteroalkyldiyl, substitutedcycloheteroalkyldiyl, heteroaryldiyl, substituted heteroaryldiyl,heteroarylalkyldiyl, substituted heteroarylalkyldiyl, heteroalkyldiyl orsubstituted heteroalkyldiyl; R⁴⁷ is hydrogen, alkyl, substituted alkyl,arylalkyl or substituted arylalkyl; R² is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, alkylamino, substituted alkylamino,alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substitutedalkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl,substituted alkylthio, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, aryloxy, substituted aryloxy, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy, or optionally, R⁴⁷ and R² taken together are alkyldiyl orsubstituted alkyldiyl; R³ and R⁶ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl; R⁴ and R⁵ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or optionally,R⁴ and R⁵ taken together are alkyldiyl, substituted alkyldiyl,heteroalkyldiyl, substituted heteroalkyldiyl, or together with thecarbon atom to which they are attached form a bridged cycloalkyl ring;R⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; R⁴⁸ is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl; R⁴⁹, R⁵⁰, R⁵¹ and R⁵² are independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, acyloxy, substituted acyloxy, amino, alkylamino,substituted alkylamino, alklysulfinyl, substituted alkylsulfinyl,alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substitutedalkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy,carbamoyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy and hydroxy, or optionally, R⁴⁹ and R⁵⁰, or R⁵¹ and R⁵²independently, together with the carbon atom(s) to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring, or optionally R⁴⁹ and R⁵¹, R⁵⁰ andR⁵², or R⁴⁹ and. R⁵² independently, together with the carbon atom(s) towhich they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring.
 3. The compoundof claim 1 having the formula:

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: n is 0 or 1; Y is O or S; X is alkyldiyl, substitutedalkyldiyl, arylalkyldiyl, substituted arylalkyldiyl, aryldiyl,substituted aryldiyl, cycloheteroalkyldiyl, substitutedcycloheteroalkyldiyl, heteroaryldiyl, substituted heteroaryldiyl,heteroarylalkyldiyl, substituted heteroarylalkyldiyl, heteroalkyldiyl orsubstituted heteroalkyldiyl; R⁴⁷ is hydrogen, alkyl, substituted alkyl,arylalkyl or substituted arylalkyl; R² is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, alkylamino, substituted alkylamino,alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substitutedalkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl,substituted alkylthio, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, aryloxy, substituted aryloxy, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy, or optionally, R⁴⁷ and R² taken together are alkyldiyl orsubstituted alkyldiyl; R³ and R⁶ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl; R⁴ and R⁵ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or optionally,R⁴ and R⁵ taken together are alkyldiyl, substituted alkyldiyl,heteroalkyldiyl, substituted heteroalkyldiyl, or together with thecarbon atom to which they are attached form a bridged cycloalkyl ring;R⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; R⁴⁸ is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl; R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³ and R⁵⁴ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl,acylamino, substituted acylamino, acyloxy, substituted acyloxy, amino,alkylamino, substituted alkylamino, alklysulfinyl, substitutedalkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio,substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substitutedaryloxy, carbamoyl, cyano, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino,substituted dialkylamino, halo, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy,heteroaryloxy, substituted heteroaryloxy and hydroxy, or optionally, R⁴⁹and R⁵⁰, R⁵¹ and R⁵², or R⁵³ and R⁵⁴, independently, together with thecarbon atom(s) to which they are attached form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring, oroptionally, R⁴⁹ and R⁵¹, R⁵⁰ and R⁵², R⁴⁹ and R⁵², R⁵¹ and R⁵³independently, together with the carbon atom(s) to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring, or optionally, R⁵² and R⁵⁴, R⁵¹ andR⁵⁴, R⁵² and R⁵³ independently, together with the carbon atom(s) towhich they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring.
 4. The compoundof claim 1 having the formula:

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: n is 0 or 1; Y is O or S; X is alkyldiyl, substitutedalkyldiyl, arylalkyldiyl, substituted arylalkyldiyl, aryldiyl,substituted aryldiyl, cycloheteroalkyldiyl, substitutedcycloheteroalkyldiyl, heteroaryldiyl, substituted heteroaryldiyl,heteroarylalkyldiyl, substituted heteroarylalkyldiyl, heteroalkyldiyl orsubstituted heteroalkyldiyl; R⁴⁷ is hydrogen, alkyl, substituted alkyl,arylalkyl or substituted arylalkyl; R² is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, alkylamino, substituted alkylamino,alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substitutedalkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl,substituted alkylthio, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, aryloxy, substituted aryloxy, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy, or optionally, R⁴⁷ and R² taken together are alkyldiyl orsubstituted alkyldiyl; R³ and R⁶ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl; R⁴ and R⁵ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or optionally,R⁴ and R⁵ taken together are alkyldiyl, substituted alkyldiyl,heteroalkyldiyl, substituted heteroalkyldiyl, or together with thecarbon atom to which they are attached form a bridged cycloalkyl ring;R⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; R⁴⁸ is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl; R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl,acylamino, substituted acylamino, acyloxy, substituted acyloxy, amino,alkylamino, substituted alkylamino, alklysulfinyl, substitutedalkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio,substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substitutedaryloxy, carbamoyl, cyano, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino,substituted dialkylamino, halo, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy,heteroaryloxy, substituted heteroaryloxy and hydroxy, or optionally, R⁴⁹and R⁵⁰, R⁵¹ and R⁵², R⁵³ and R⁵⁴, R⁵⁵ and R⁵⁶, independently, togetherwith the carbon atom(s) to which they are attached form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring, or optionally R⁴⁹ and R⁵¹, R⁵⁰ and R⁵², R⁴⁹ and R⁵², R⁵¹ and R⁵³independently, together with the carbon atom(s) to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring, or optionally, R⁵² and R⁵⁴, R⁵¹ andR⁵⁴, R⁵² and R⁵³ independently, together with the carbon atom(s) towhich they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring, or optionally,R⁵³ and R⁵⁵, R⁵⁴ and R⁵⁶, R⁵³ and R⁵⁶ and R⁵⁴ and R⁵⁵ independently,together with the carbon atom(s) to which they are attached form acycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring.
 5. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: n is 0 or 1; Y is O or S; X is alkyldiyl, substitutedalkyldiyl, arylalkyldiyl, substituted arylalkyldiyl, aryldiyl,substituted aryldiyl, cycloheteroalkyldiyl, substitutedcycloheteroalkyldiyl, heteroaryldiyl, substituted heteroaryldiyl,heteroarylalkyldiyl, substituted heteroarylalkyldiyl, heteroalkyldiyl orsubstituted heteroalkyldiyl; R⁴⁷ is hydrogen, alkyl, substituted alkyl,arylalkyl or substituted arylalkyl; R² is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, alkylamino, substituted alkylamino,alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substitutedalkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl,substituted alkylthio, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, aryloxy, substituted aryloxy, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy, or optionally, R⁴⁷ and R² taken together are alkyldiyl orsubstituted alkyldiyl; R³ and R⁶ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl; R⁴ and R⁵ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or optionally,R⁴ and R⁵ taken together are alkyldiyl, substituted alkyldiyl,heteroalkyldiyl, substituted heteroalkyldiyl, or together with thecarbon atom to which they are attached form a bridged cycloalkyl ring;R⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; R⁴⁸ is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl; and R⁵⁷ and R⁵⁸ are independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,acylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl,or optionally R⁵⁷ and R⁵⁸ together with the carbon atoms to which theyare attached form an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring.
 6. The compound of claim 1 having theformula:

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: n is 0 or 1; Y is O or S; X is alkyldiyl, substitutedalkyldiyl, arylalkyldiyl, substituted arylalkyldiyl, aryldiyl,substituted aryldiyl, cycloheteroalkyldiyl, substitutedcycloheteroalkyldiyl, heteroaryldiyl, substituted heteroaryldiyl,heteroarylalkyldiyl, substituted heteroarylalkyldiyl, heteroalkyldiyl orsubstituted heteroalkyldiyl; R⁴⁷ is hydrogen, alkyl, substituted alkyl,arylalkyl or substituted arylalkyl; R² is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, alkylamino, substituted alkylamino,alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substitutedalkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl,substituted alkylthio, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, aryloxy, substituted aryloxy, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy, or optionally, R⁴⁷ and R² taken together are alkyldiyl orsubstituted alkyldiyl; R³ and R⁶ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl; R⁴ and R⁵ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or optionally,R⁴ and R⁵ taken together are alkyldiyl, substituted alkyldiyl,heteroalkyldiyl, substituted heteroalkyldiyl, or together with thecarbon atom to which they are attached form a bridged cycloalkyl ring;R⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; R⁴⁸ is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl; R⁴⁹ and R⁵⁰ are independently selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, acyl, substituted acyl, acylamino, substitutedacylamino, acyloxy, substituted acyloxy, amino, alkylamino, substitutedalkylamino, alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl,substituted alkylsulfonyl, alkylthio, substituted alkylthio,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy,carbamoyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy and hydroxy, or optionally, R⁴⁹ and R⁵⁰ together with thecarbon atom(s) to which they are attached form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; andR⁵⁷ and R⁵⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acylamino, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl, or optionally R⁵⁷ and R⁵⁸ together with thecarbon atoms to which they are attached form an aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring.
 7. The compoundof claim 1 having the formula:

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: n is 0 or 1; Y is O or S; X is alkyldiyl, substitutedalkyldiyl, arylalkyldiyl, substituted arylalkyldiyl, aryldiyl,substituted aryldiyl, cycloheteroalkyldiyl, substitutedcycloheteroalkyldiyl, heteroaryldiyl, substituted heteroaryldiyl,heteroarylalkyldiyl, substituted heteroarylalkyldiyl, heteroalkyldiyl orsubstituted heteroalkyldiyl; R⁴⁷ is hydrogen, alkyl, substituted alkyl,arylalkyl or substituted arylalkyl; R² is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, alkylamino, substituted alkylamino,alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substitutedalkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl,substituted alkylthio, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, aryloxy, substituted aryloxy, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy, or optionally, R⁴⁷ and R² taken together are alkyldiyl orsubstituted alkyldiyl; R³ and R⁶ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl; R⁴ and R⁵ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or optionally,R⁴ and R⁵ taken together are alkyldiyl, substituted alkyldiyl,heteroalkyldiyl, substituted heteroalkyldiyl, or together with thecarbon atom to which they are attached form a bridged cycloalkyl ring;R⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; R⁴⁸ is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl; R⁵³ and R⁵⁴ are independently selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, acyl, substituted acyl, acylamino, substitutedacylamino, acyloxy, substituted acyloxy, amino, alkylamino, substitutedalkylamino, alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl,substituted alkylsulfonyl, alkylthio, substituted alkylthio,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy,carbamoyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy and hydroxy, or optionally, R⁵³ and R⁵⁴ together with thecarbon atom(s) to which they are attached form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; andR⁵⁷ and R⁵⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acylamino, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl, or optionally R⁵⁷ and R⁵⁸ together with thecarbon atoms to which they are attached form an aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring.
 8. The compoundof claim 1 having the formula:

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: n is 0 or 1; Y is O or S; X is alkyldiyl, substitutedalkyldiyl, arylalkyldiyl, substituted arylalkyldiyl, aryldiyl,substituted aryldiyl, cycloheteroalkyldiyl, substitutedcycloheteroalkyldiyl, heteroaryldiyl, substituted heteroaryldiyl,heteroarylalkyldiyl, substituted heteroarylalkyldiyl, heteroalkyldiyl orsubstituted heteroalkyldiyl; R⁴⁷ is hydrogen, alkyl, substituted alkyl,arylalkyl or substituted arylalkyl; R² is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, alkylamino, substituted alkylamino,alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substitutedalkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl,substituted alkylthio, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, aryloxy, substituted aryloxy, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy, or optionally, R⁴⁷ and R² taken together are alkyldiyl orsubstituted alkyldiyl; R³ and R⁶ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl; R⁴ and R⁵ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or optionally,R⁴ and R⁵ taken together are alkyldiyl, substituted alkyldiyl,heteroalkyldiyl, substituted heteroalkyldiyl, or together with thecarbon atom to which they are attached form a bridged cycloalkyl ring;R⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; R⁴⁸ is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl; R⁴⁹, R⁵⁰, R⁵¹ and R⁵² are independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, acyloxy, substituted acyloxy, amino, alkylamino,substituted alkylamino, alklysulfinyl, substituted alkylsulfinyl,alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substitutedalkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy,carbamoyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy and hydroxy, or optionally, R⁴⁹ and R⁵⁰, or R⁵¹ and R⁵²independently, together with the carbon atom(s) to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring, or optionally R⁴⁹ and R⁵¹, R⁵⁰ andR⁵², or R⁴⁹ and R⁵², independently, together with the carbon atom(s) towhich they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring; and R⁵⁷ and R⁵⁸are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, acylamino, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl, or optionally R⁵⁷ and R⁵⁸ together with thecarbon atoms to which they are attached form an aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring.
 9. The compoundof claim 1 having the formula:

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: n is 0 or 1; Y is O or S; X is alkyldiyl, substitutedalkyldiyl, arylalkyldiyl, substituted arylalkyldiyl, aryldiyl,substituted aryldiyl, cycloheteroalkyldiyl, substitutedcycloheteroalkyldiyl, heteroaryldiyl, substituted heteroaryldiyl,heteroarylalkyldiyl, substituted heteroarylalkyldiyl, heteroalkyldiyl orsubstituted heteroalkyldiyl; R⁴⁷ is hydrogen, alkyl, substituted alkyl,arylalkyl or substituted arylalkyl; R² is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, alkylamino, substituted alkylamino,alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substitutedalkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl,substituted alkylthio, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, aryloxy, substituted aryloxy, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy, or optionally, R⁴⁷ and R² taken together are alkyldiyl orsubstituted alkyldiyl; R³ and R⁶ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl; R⁴ and R⁵ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or optionally,R⁴ and R⁵ taken together are alkyldiyl, substituted alkyldiyl,heteroalkyldiyl, substituted heteroalkyldiyl, or together with thecarbon atom to which they are attached form a bridged cycloalkyl ring;R⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; R⁴⁸ is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl; R⁴⁹, R⁵⁰, R⁵⁵ and R⁵⁶ are independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, acyloxy, substituted acyloxy, amino, alkylamino,substituted alkylamino, alklysulfinyl, substituted alkylsulfinyl,alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substitutedalkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy,carbamoyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy and hydroxy, or optionally, R⁴⁹ and R⁵⁰, or R⁵⁵ and R⁵⁶,independently, together with the carbon atom(s) to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring; and R⁵⁷ and R⁵⁸ are independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, acylamino, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl, or optionally R⁵⁷ and R⁵⁸ together with the carbonatoms to which they are attached form an aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring.
 10. The compoundof claim 1 having the formula:

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: n is 0 or 1; Y is O or S; X is alkyldiyl, substitutedalkyldiyl, arylalkyldiyl, substituted arylalkyldiyl, aryldiyl,substituted aryldiyl, cycloheteroalkyldiyl, substitutedcycloheteroalkyldiyl, heteroaryldiyl, substituted heteroaryldiyl,heteroarylalkyldiyl, substituted heteroarylalkyldiyl, heteroalkyldiyl orsubstituted heteroalkyldiyl; R⁴⁷ is hydrogen, alkyl, substituted alkyl,arylalkyl or substituted arylalkyl; R² is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, alkylamino, substituted alkylamino,alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substitutedalkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl,substituted alkylthio, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, aryloxy, substituted aryloxy, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy, or optionally, R⁴⁷ and R² taken together are alkyldiyl orsubstituted alkyldiyl; R³ and R⁶ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl; R⁴ and R⁵ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or optionally,R⁴ and R⁵ taken together are alkyldiyl, substituted alkyldiyl,heteroalkyldiyl, substituted heteroalkyldiyl, or together with thecarbon atom to which they are attached form a bridged cycloalkyl ring;R⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; R⁴⁸ is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl; R⁵³, R⁵⁴, R⁵⁵ and R⁵⁶ are independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino,substituted acylamino, acyloxy, substituted acyloxy, amino, alkylamino,substituted alkylamino, alklysulfinyl, substituted alkylsulfinyl,alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substitutedalkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy,carbamoyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, substitutedheteroaryloxy and hydroxy, or optionally, R⁵³ and R⁵⁴, or R⁵⁵ and R⁵⁶,independently, together with the carbon atom(s) to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring, or optionally, R⁵³ and R⁵⁵, R⁵⁴ andR⁵⁶, R⁵³ and R⁵⁶ and R⁵⁴ and R⁵⁵ independently, together with the carbonatom(s) to which they are attached form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; andR⁵⁷ and R⁵⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acylamino, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl, or optionally R⁵⁷ and R⁵⁸ together with thecarbon atoms to which they are attached form an aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring.
 11. The compoundof claim 1 wherein n is
 0. 12. The compound of claim 1 wherein Y is Oand R⁷is hydrogen.
 13. The compound of claim 1 wherein R⁴ and R⁵ aretaken together with the carbon atom to which they are attached to form acycloalkyl ring.
 14. The compound of claim 13 wherein the cycloalkylring is a cyclohexyl ring.
 15. The compound of claim 1 wherein R⁴ isalkyl and R⁵is hydrogen.
 16. The compound of claim 1 wherein R⁴ ishydrogen and R⁵is alkyl.
 17. The compound of claim 15 wherein the alkylgroup is an isobutyl group.
 18. The compound of claim 16 wherein thealkyl group is an isobutyl group.
 19. The compound of claim 1 wherein Xis —(CH₂)_(n)— and n is an integer ranging from 2 to
 5. 20. The compoundof claim 19 wherein X is —(CH₂)₅—.
 21. The compound of claim 19 whereinR⁴⁸ is hydrogen.
 22. A composition comprising a compound of claim 1 anda pharmaceutically acceptable carrier, diluent, excipient or adjuvant.23. A composition comprising a compound of claim 2 and apharmaceutically acceptable carrier, diluent, excipient or adjuvant. 24.A composition comprising a compound of claim 3 and a pharmaceuticallyacceptable carrier, diluent, excipient or adjuvant.
 25. A compositioncomprising a compound of claim 4 and a pharmaceutically acceptablecarrier, diluent, excipient or adjuvant.
 26. A composition comprising acompound of claim 5 and a pharmaceutically acceptable carrier, diluent,excipient or adjuvant.
 27. A composition comprising a compound of claim6 and a pharmaceutically acceptable carrier, diluent, excipient oradjuvant.
 28. A composition comprising a compound of claim 7 and apharmaceutically acceptable carrier, diluent, excipient or adjuvant. 29.A composition comprising a compound of claim 8 and a pharmaceuticallyacceptable carrier, diluent, excipient or adjuvant.
 30. A compositioncomprising a compound of claim 9 and a pharmaceutically acceptablecarrier, diluent, excipient or adjuvant.
 31. A composition comprising acompound of claim 10 and a pharmaceutically acceptable carrier, diluent,excipient or adjuvant.
 32. A method for treating or preventing adisorder selected from epilepsy, depression, anxiety, psychosis,faintness attacks, hypokinesia, cranial disorders, neurodegenerativedisorders, panic, pain disorders, inflammatory diseases, arthritis,insomnia, gastrointestinal disorders or ethanol withdrawal symptom in apatient, the method comprising administering to a patient in needthereof a therapeutically effective amount of the compound of claim 1.33. The method of claim 32 wherein the disorder is epilepsy.
 34. Themethod of claim 32 wherein the disorder is a pain disorder.
 35. Themethod of claim 34 wherein the pain disorder is neurodegenerative painor post-herpetic pain.
 36. A method for treating or preventing adisorder selected from epilepsy, depression, anxiety, psychosis,faintness attacks, hypokinesia, cranial disorders, neurodegenerativedisorders, panic, pain disorders, inflammatory diseases, arthritis,insomnia, gastrointestinal disorders or ethanol withdrawal symptom in apatient, the method comprising administering to a patient in needthereof a therapeutically effective amount of the compound of any one ofclaims 2-10.
 37. The method of claim 36 wherein the disorder isepilepsy.
 38. The method of claim 36 wherein the disorder is a paindisorder.
 39. The method of claim 38 wherein the pain disorder isneurodegenerative pain or post-herpetic pain.